On November 6, 2013 members of the Sterilization Packaging Manufacturers Council (SPMC) technical group conducted a webinar called “Sterilization: A Packaging Perspective.” There were a number of questions left unanswered in the time allotted. Several questions were similar in nature and are being addressed together in order to provide a more concise response. The SPMC invites all readers to visit the Technical Assistance section of the SPMC website (www.sterilizationpackaging.org) to add new questions or request expansion of any published answers.
Q. How do I determine the required amount of breathable area of a package?
A: Total package porosity, which is a function of gas flow and surface area, is critical to the sterilization and aeration phases of Ethylene Oxide (EtO) gas sterilization processes. Whether designing a port, the size of a secondary label, or optimizing a cycle, there is no generic answer for all packages and types. The general rule, of course, is that more porosity is better. In other words, as the porosity increases, cycle and aeration times can be reduced, and a smaller porous area maybe sufficient. However, all are package, product, and cycle dependent. Without knowing the details of a specific application, it is hard to predict the required porosity of an individual package design. Theoretical calculations for porous area require knowledge of some key package and cycle characteristics. Breathable surface area, package volume, secondary and tertiary packaging, and peel force are all factors that determine porosity limitations. Information regarding the worst-case average porous area, the volume of the package, and the gas exchange rate for each part of the EtO cycle at a minimum is needed. Even though there have been several attempts to create such predictive models, in the end sterilization testing is still required to qualify a package design. Product families of worst-case configurations and cycles are helpful to limit the amount of testing, but optimization of package porosity for an EtO cycle is often an iterative process.
Q. How should I go about packaging a moisture-sensitive component for EtO sterilization?
A: Two common package design approaches are double pouching and vented pouches. Double pouching with an inner breathable pouch and outer barrier pouch, such as foil, is a common option. The inner breathable pouch is EtO sterilized and then placed in outer foil pouch. In this case, only the inside of the primary sterile barrier system (the inner pouch) is sterile. Therefore, aseptic presentation can only be performed with the inner pouch. Package labeling should clarify this aspect to the user. A vented foil pouch is a second option. The pouch is EtO sterilized and sealed, excluding the vent, which is removed by cutting. What remains is an all-foil pouch. Since the package is designed with the extra vent area that is later removed, a larger pouch size is required. The benefits to this approach are single sterilization and less packaging material than double pouching. In some moisture-sensitive components of kit packs, a product can be packaged in a fully nonporous barrier material. These products are often radiation sterilized first and typically vacuum packaged in order to remove air. Trapped air within the package would expand under the pressure changes in EtO cycles and potentially rupture seals or expand enough to open the kit pack closure, thereby compromising the kit.
Q. Please address nontraditional sterilization methods.
A. The SPMC technical group received several questions on ozone and plasma sterilization related specifically to the efficacy of these sterilization methods. Since the SPMC group is focused on healthcare packaging, the intent of the Webcast was to provide the audience with a general understanding of the impact different sterilization methods have on packaging materials. As a packaging industry group, we do not offer a position on the efficacy of different sterilization methods. For that we recommend you reach out to sterilization companies for their expertise. We do, however, have the expertise to provide guidance on packaging considerations. From a packaging perspective, both ozone and gas plasma require a porous web to allow the sterilization gas to enter and exit the sealed package. Since these sterilization processes are similar to EtO, the same types of packaging considerations are applicable from a porosity perspective. Material performance in these sterilization methods do vary. There are limits to the use of cellulosic-based material, for example, in plasma sterilization, while this restriction does not apply in EtO. For further information on sterilization practices and FDA-approved methods, refer to CDC and FDA Websites. The links listed below can provide starting points for this guidance:
Q. Is it preferred to use the bubble test to validate package integrity? Is it appropriate to use the blue dye penetration test post product conditioning (i.e., environmental / transit)?
A: ASTM F2096 (bubble leak testing) is a commonly used test to validate whole package integrity post distribution conditioning. It is a simple test that requires little capital investment in equipment, but is limited in sensitivity of detection of holes or channels to 0.010 in. (250 µm). ASTM 1929 (dye penetrant testing), on the other hand, is a seal integrity test, which has a higher degree of sensitivity at 0.002 in. (50 µm). ASTM F3039 is a new dye penetration method for evaluating nonporous package seals. These can be utilized in post product conditioning, but are limited to seal evaluation only. A whole package integrity test is still required to evaluate potential holes in the rest of the package.
Q. In light of the observation that e-beam does not penetrate as deeply as gamma, is e-beam also limited by directional exposure? And can the lower penetration depth be overcome with multiple runs or higher doses?
A: The main factors governing the penetration depth of e-beam are the mass and charge of an electron. Gamma rays emitted by a 60 Co source in a gamma sterilization process are not charged and do not have mass. As an electron interacts with the product being sterilized, it interacts with the material and transfers its energy rather quickly and is therefore not able to penetrate the product to the same degree as a gamma ray. Therefore, the depth of penetration of e-beam for a given material can only be governed by the accelerating voltage used in the e-beam process, much like the penetration of a bullet in increased by increasing its velocity. Directional exposure concerns are typically only encountered in sterilization processes in which surface sterilization is required. This is true, for instance, in UV sterilization. Only the surfaces of the part that are in a direct line with the UV source will be sterilized. This can be mitigated with multiple sources or with product rotation. If an e-beam process has been designed and is being used to sterilize the surface of a product only (i.e., a low accelerating voltage is being used) then consideration will need to be given to ensuring that all product surfaces are exposed. However, if the e-beam process has been designed and is being used to sterilize the entire product (for instance, a sterile package containing a 3-D part with complex geometry and internal cavities) the directional exposure concerns are minimized, although the process may include product rotation to ensure dose uniformity. The sterilization process will still need to be validated to ensure that appropriate bioburden reduction levels are achieved.
Q. The radiation stability of a number of materials commonly used in sterile packaging of medical and pharmaceutical products was discussed. Where can I find this information for other materials, such as PVDF and polycarbonate?
A: A number of reference documents were highlighted during that Webinar that bear mentioning again: • AAMI TIR17:2008 – Compatibility of materials subject to sterilization. • AAMI TIR22:2007 – Guidance for ANSI/AAMI/ISO 11607, Packaging for terminally sterilized medical devices. • International Atomic Energy Agency: Guidelines for industrial sterilization of disposable medical products (Co 60 gamma irradiation), TEC DOC-539, Vienna IAEA 1990. • Trends in Radiation Sterilization of Healthcare Products, Pub-1313. Vienna IAEA 2008. These documents, and others, provide helpful guidance related to the effect of sterilization on materials, as part of a fuller discussion of sterilization processes and considerations. According to these references, polycarbonate is considered to be radiation-stable, owing to the aromatic nature of the chemical structure (contain conjugated planar ring systems with delocalised pi electron clouds). Some grades may undergo discoloration, although significant strides have been made by resin and additive producers to minimize, mitigate, or eliminate this effect. Fluoropolymers, like PTFE and PCTFE, are known to be unstable to radiation sterilization. Other fluoropolymers (such as PVDF) are more stable to radiation sterilization, although, as always, product validation and verification are expected over the intended shelf-life.
Q. What are the advantages of using e-beam over gamma sterilization, or vice versa?
A: There is no easy answer to this question, unfortunately, since the best place to have a discussion about advantages and/or disadvantages of e-beam and gamma is in the context of a specific product and its manufacturing process. It is critical that consideration of the sterilization requirements be conducted early in the product and process development cycle. In general, both e-beam and gamma are low-temperature processes compared with heat-based sterilization options like steam sterilization. While e-beam may induce a slightly greater temperature rise in materials compared to gamma at high e-beam dose rates, it is also generally somewhat less damaging to materials. Penetration depth differences between e-beam and gamma (gamma penetrates further than e-beam at a given density) are best viewed not on the advantage/disadvantage scale but as product and process design flexibilities. The same can be said of batch vs in-line; a batch gamma process may be most appropriate in one situation, while in-line e-beam sterilization may be better suited to a different product. Given these, and many other considerations, the advisability and importance of involving in-house and external sterilization science experts in the earliest phases of the product and package design process cannot be stressed too much.