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Dear Readers, Welcome to the latest issue of Micr
The modern landscape of biopharmaceutical manufacturing is dominated by the rapid introduction of single-use technologies (SUT) and their associated components.
Disposable bioprocessing bags, mixing systems, tubing assembly, filtration systems, connectors, and fluid transfer components are utilized to manufacture monoclonal antibodies, vaccines, cell therapies, gene therapies, and recombinant proteins.
Highly complex and sophisticated polymers utilized in biopharmaceutical manufacturing require the final sterilization of these SUTs. Gamma irradiation has been the dominant technology for over four decades; however, that may be changing.
High-energy X-ray sterilization technologies may provide competitive advantages from a manufacturing and logistics point of view for ensuring the same level of sterility assurance as gamma irradiation.
All technologies for radiation sterilization employ damage to cellular and DNA structures from ionization to kill microorganisms. Gamma rays and X-rays share this mechanism of DNA damage and cause sterilization without leaving a radioactive residue.
Gamma irradiation is delivered from radioisotopes of cobalt-60. ISO 11137 standard defines the range of sterilization doses as 25 to 40 kGy. High-energy X-ray sterilization systems utilize electron accelerators in the range of 5 to 7.5 MeV for sterilization. When high-energy electrons strike a metallic target, high-energy bremsstrahlung X-ray similar to cobalt-60 gamma radiation is produced.
The equivalence in the biological effectiveness of both technologies allows sterilization dose validation to be transferred over with minor modifications to the process.
Acceptance of X-ray sterilization by global regulatory agencies has grown substantially in the last ten years. International standards ISO 11137 Parts 1 – 3 recognize gamma, electron beam (E-beam), and X-ray as equivalent radiation sterilization modalities.
Both the U.S. FDA and European regulators have accepted X-ray sterilization providing manufacturers demonstrate adequate dose mapping, bioburden determination, process controls, and validation of a sterility assurance level (SAL) of 10⁻⁶.
Leading global biopharmaceutical suppliers have qualified numerous single-use assemblies sterilized by X-ray irradiation demonstrating increasing acceptance of the technology by global regulatory agencies.
The major components of bioprocess bags include polyethylene (PE), ethylene vinyl acetate (EVA), ethylene vinyl alcohol (EVOH), ultra-low-density polyethylene (ULDPE), polypropylene (PP), thermoplastic elastomers (TPE), and silicone elastomers. During radiation sterilization polymer chain scission, cross-linking, and oxidation may occur.
The extent of these changes may depend on the chemistry of the polymer used, the stabilizer system, the presence or absence of oxygen, and the dose absorbed.
There are many studies in the literature that have compared the effects of X-ray irradiation to gamma irradiation, and these reveal that there are similar effects. Polymer modifications due to X-ray sterilization do not appreciably impact mechanical properties of the materials and polymer films up to 50 kGy.
One benefit of X-ray over gamma irradiation, is that X-ray systems deliver radiation faster, therefore reducing the length of time the polymer multilayer films are exposed to an oxidative environment. This has the potential of decreasing the oxidative degradation of polyethylene.
Extraction studies on biopharmaceutical systems have been conducted to identify and better understand the migration and potential degradation of materials in contact with therapeutic proteins.
Evidence seems to indicate that, in terms of extractable profiles, X-ray sterilization parallels gamma sterilization. The production of a number of compounds following X-ray treatment have been documented.
These include: organic oxidation products, antioxidants, oligomers, and low-molecular-weight degradation compounds, which are for the most part, similar to, or less than, for gamma irradiation. Variability in formulation is the main contributor to differences in these compounds.
The integrity of the heat sealed bag also must be considered. The strength of the seal is primarily determined by the polymer and the parameters of the sealing process and is not related to the choice of the sterilization method.
Several studies have shown that properly optimized X-ray sterilization process maintains seal peel strength, burst pressure, and weld integrity that are equivalent to assemblies of gamma treated products.
The differences in manufacturing economics of X-ray and gamma sterilization are significant. Gamma plants require the secure handling of radioactive sources of cobalt-60, massive shielding, continual oversight by the regulation agencies, and long, expensive commissioning periods. The construction of one of these plants is generally in the range of US$20–40 million.
The X-ray sterilization systems make no use of radioactive sources, and therefore have less economic burden and more flexible licensing, and lower operating costs since there are no isotopes to replace.
However, these systems still have a significant cost due to the capital expenditure on the high energy electron accelerator. The primary limitation is the efficiency of X-ray conversion which is approximately 8–15% versus direct electron beam systems.
Though there is a high disadvantage of electricity consumption versus E-beam sterilization due to the conversion efficiency, improvements in accelerator technologies are slowly diminishing this disadvantage.
Quality assurance for X-ray sterilization is the same as for gamma irradiation. Manufacturers perform dosimeter calibration, dose mapping, routine monitoring, microbial validation, equipment qualification and periodic revalidation per ISO 11137.
Newer X-ray sterilization units include digital control systems for real time beam monitoring and dose, and electronic batch records to improve process traceability and provide automated dose verification.
There is no radioactive decay for the X-ray source and so there is no decrease in radiation output over time, making dose consistency easier to control throughout the lifespan of the equipment. This also simplifies dose consistency in gamma sterilization equipment.
Constrained supplies of cobalt-60 and increasing scrutiny on the use of radioactive materials is likely to increase interest in X-ray sterilization in the life science industry.
It is particularly valuable for high value single-use bioprocess assemblies and biomedical polymer components due to its favorable regulation, polymer compatibility, and increasing microbial efficacy.
Though gamma irradiation is anticipated to remain a key sterilization technology, over the coming years, improvement in the efficiency of accelerator technology and digital control systems for X-ray sterilization are expected to make X-ray sterilization the preferred choice for biopharmaceutical manufacturers.
For manufacturers looking for stable supply chains and sustainable solutions for equipment sterilization, X-ray technology is a considerable development in radiation processing over the last 20 years.
Authored By: Priyabrata Pattnaik
Chief Executive Officer (CEO)
Mail Id: [email protected]
