Regulators require pharmaceutical primary packaging to be sterile. To achieve this, radiation sterilization is one of the most common methods, as it is reproducible and leaves no residues.
Requirements for the sterility of primary pharmaceutical packaging
The sterilization or decontamination of packaging is indispensable in many manufacturing processes to ensure reproducible results as well as the quality and safety of the end products. The sterilization of pharmaceutical primary packaging is subject to comparatively strict regulations. Sterility is defined according to DIN EN 556: According to this standard, packaging is considered sterile only if the theoretical probability of finding a living microbe per object does not exceed 1 in 1,000,000. While a microbe-reduced state is sufficient for food packaging and regulated accordingly by law, sterility is required for pharmaceutical primary packaging. An important reason for this is its role: not only to enclose a product and facilitate transport, but also to protect the product from external influences during storage and use.
Furthermore, pharmaceutical primary packaging always comes into direct contact with the drug. For example, packaging materials for liquid or moist drug forms must be sterile prior to filling, as they would otherwise provide ideal growth conditions for microorganisms in a closed system due to the moisture they contain. Properly sterilized packaging is therefore not only required by law but is essential for the protection of patients.
Benefits of radiation sterilization of packaging
Various methods and technologies can be used to sterilize primary pharmaceutical packaging. Common methods include ethylene oxide fumigation (ETO sterilization) as well as sterilization using beta (E-Beam), gamma, or X-ray radiation. The goal of any sterilization process is to prevent the reproduction of pathogenic microorganisms and to destroy them.
Treatment with ionizing beta or gamma radiation is one of the most common methods, as it offers several advantages. Unlike ETO sterilization, the process is chemical-free, leaves no residues on or in the product, and does not cause a significant increase in temperature during the process. Since the radiation dose can be precisely applied, radiation sterilization is also reliable and reproducible.
The process can also be carried out relatively quickly and integrates well into existing logistics processes: With E-Beam, individual packages can be irradiated within a few seconds. Irradiation in gamma facilities takes several hours but is often the preferred choice because gamma rays, due to their high penetration depth, are capable of penetrating entire pallets or containers even with high packing density.
In electron accelerators and gamma facilities, the entire product is thus irradiated, and not just the surface of the packaging material. This ensures that the interiors of sealed packages are also reliably sterilized - a prerequisite for all products that are subsequently filled under aseptic conditions or into which no foreign organisms may be introduced. Not only are viruses and bacteria such as salmonella and E. coli reliably killed, but also mold spores, which have a thicker cell wall and are resistant to UV-C radiation, for example.
How material affects the sterilization of primary pharmaceutical packaging
Many pharmaceutical primary packaging materials can be treated in a gamma facility or an electron accelerator prior to filling. These include, for example, ampoules, pouches, bottles, cans, and tubes. However, whether radiation sterilization is actually the method of choice depends largely on the material composition of the product. This is because electron and gamma rays can alter the material properties of the products, particularly in the case of many polymer materials. This depends both on the material itself and on the irradiation dose used.
This is due to chemical reactions induced by the radiation energy, such as cross-linking or degradation reactions. Plastics such as polyethylene (PE) and cycloolefin copolymers (COC or COP) are very well suited, for example. Other materials are only suitable to a limited extent because their properties can change - glass, for example, discolors under irradiation.
In some cases where radiation sterilization cannot be used due to the materials involved, ethylene oxide fumigation is the method of choice. ETO sterilization is a chemical process with several process parameters, including gas concentration, humidity, temperature, and diffusion time. However, powdered substances, products that must not become damp, or those packaged in gas-tight containers are unsuitable for this form of sterilization. Furthermore, fumigation involves a degassing phase lasting several days - meaning the products cannot be released to the market immediately.
An overview of common polymers and their material resistance can be found here: www.bgs.eu/en/radiation-sterilization/
Radiation sterilization in transport packaging
Due to the complex equipment, high safety standards, and regulations associated with irradiation, manufacturers typically outsource the sterilization of their products to specialized service providers. Using the example of a plastic nasal spray dispenser, the basic process of irradiation by service providers such as BGS Beta-Gamma-Service can be understood.
The complete system or individual components - empty bottle, atomizer, cap - are shipped by the manufacturer. Upon delivery to the service provider, the products are treated in their transport packaging. There is no unpacking or repacking. Immediately after irradiation, the products undergo quality assurance inspection and are released. They are then shipped to the nasal spray manufacturer for further processing with no external changes. This makes radiation sterilization easy to plan and suitable for time-sensitive supply chains.
Validation of radiation sterilization of pharmaceutical packaging in three steps
Pure irradiation is preceded by a comprehensive validation process: the customer and service provider work closely together to assess the application of radiation sterilization for the respective product. This process is divided into three parts: microbiological, dosimetric, and application-specific validation.
In addition to determining the microbial load and the sterilization dose required to convert a non-sterile product into a sterile one, the primary focus is on determining the dose distribution. This is not only product-specific but also configuration-specific and therefore always relates to the arrangement of the nasal spray bottles in the packaging. It is also important to clarify to what extent the properties and functions of the material are altered by irradiation.
Once the processes have been established and details such as packing density, packaging material, carton , and product orientation have been defined, the result is fully reproducible and routine irradiation can begin. However, this also means that if changes are made to the product or its manufacturing process at a later stage, these must be evaluated by the manufacturer, and the selected procedure may need to be revalidated.
Where radiation sterilization is used
Beta and gamma rays are not only used to sterilize primary pharmaceutical packaging. Microbial reduction with reproducible results and safe end products are also necessary and in some cases legally required - for the packaging of food, animal feed, and personal care products to ensure consumer protection.
If large product ranges are to be sterilized or undergo germ reduction, it makes sense to consider processing classes. Items that can be irradiated under the same conditions are assigned to a processing class. This has the advantage that no new qualification is necessary for additional products and existing processing classes.
Learn more about radiation sterilization of packaging materials from BGS: www.bgs.eu/en/radiation-sterilization/packaging-material/
