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Environmental Compliance and Control for Radiopharmaceutical Production
Published in Michael Ljungberg, Handbook of Nuclear Medicine and Molecular Imaging for Physicists, 2022
Ching-Hung Chiu, Ya-Yao Huang, Wen-Yi Chang, Jacek Koziorowski
Second, from the review of radiation protection, syringe shielding is the common approach for dispensing, distribution, and administration of radiopharmaceuticals. Generally, sterility assurance level (SAL) is required to be 10−6 and 10−3, for drug products with terminal sterilization and aseptic manufacturing, respectively. However, such strict SAL requirements for intravenously administered radiopharmaceuticals that are usually administered within hours of preparation is debatable and thus results in troublesome decontamination of syringe shielding. Recently, a SAL of 10−2 for radiopharmaceuticals has been proposed [26] and has been adopted in Dutch hospital pharmacies for extemporaneous aseptic preparations of parenterals [28]. This proposed SAL value has proved to be consistent with the proposed contamination recovery rate in a class A (ISO 5) aseptic environment of the USP without huge numbers of media fills [26, 29].
Effect of gamma sterilization on the properties of microneedle array transdermal patch system
Published in Drug Development and Industrial Pharmacy, 2020
Honnavar Parthasarathy Swathi, Vishwanath Anusha Matadh, Jhimli Paul Guin, Sathyanarayana Narasimha Murthy, Paranjothy Kanni, Lalit Varshney, Sarasija Suresh, Hagalavadi Nanjappa Shivakumar
Considering the limitations of the above-mentioned MNs, we plan to develop soluble polymeric MNs composed of water-soluble matrix materials that would dissolve in the skin to instantaneously release the bolus. Polymers that can get noncovalently bound are known to be promising biomaterials in development of soluble MNs due to their biocompatibility and low manufacturing cost. Drug-loaded polymeric MNs are invariably fabricated using polymers that are generally regarded as safe (GRAS listed) by US FDA. These MNs are known to dissolve instantaneously after insertion, obviating the need for disposal of hazardous sharp needles following application. It is a general consensus that MN’s need to be sterile as they penetrate into the viable epidermal and the dermal regions of the skin [8]. However, it has to be noted that dry heat sterilization was found to be unsuitable as it resulted in irreversible destruction of the polymeric MNs. The MNs lost the mechanical strength, became soft and malleable and lost the needle structure on exposure to dry heat. Similarly, moist heat sterilization caused complete dissolution of the polymeric MNs. To overcome the limitations associated with the conventional sterilizing methods, ionizing radiations have been widely employed as a terminal sterilization method for biomedical devices. Gamma sterilization in particular appears to be a viable option when other methods of sterilizations are known to damage the integrity of the medical devices [8]. Gamma radiation is ionizing radiation that has the ability to easily penetrate the bulk of the material to render them sterile. It is advantageous as it can be applied to the products packed in final containers without significant increase in temperature. Among several sterilization methods, gamma sterilization is considered to be the method of choice for thermosensitive drugs [9]. A dose of 25 kGy is known to ensure a sterility assurance level (SAL) of 10−6 as per the Pharmacopeia [10]. In this context, gamma sterilization was found to offer potential solution to the problems encountered by conventional sterilization methods.
Bridging the gap between fundamental research and product development of long acting injectable PLGA microspheres
Published in Expert Opinion on Drug Delivery, 2022
Xun Li, Zhanpeng Zhang, Alan Harris, Lin Yang
Therefore, aim at specific API, feasibility studies on the influence of dose of gamma ray or E-beam on the critical quality attributes of PLGA microspheres need to be performed at first. In this study, the dose can be set at different kilogray (kGy) units, which quantify the absorbed energy of radiation. The critical quality attributes, including the appearance, API assay content, impurities, in vitro release, particle size distribution, water content, PLGA molecule weight and glass transition temperature are measured before and after irradiation. The difference and change trend indicate whether the dose and irradiation approach are feasible. Currently, there are no standard protocols of gamma irradiation and E-beams irradiation for PLGA microspheres sterilization. A major challenge in sterilizing PLGA microspheres is the generation of impurities. There are plenty of factors, such as polymer type, particle size distribution, residual solvent amount, API type and API distribution within microspheres would affect the impurity levels after sterilization. Some studies showed 25 kGy can normally achieve sterility with a sterility assurance level (SAL) of 10−6. But under 25 kGy irradiation, the color of glass vials changed into brown. Degradation and molecule weight decrease of PLGA were found. In addition, API assay content decrease while the impurities level increase. In terms of the in-vitro release rate, it is supposed to be accelerated because the polymer start to degrade after irradiation [126]. For example, gamma irradiation is usually conducted with a mean dose rate of approx. 2–3 kGy/h. The entire gamma irradiation process usually takes 10–12 hrs to ensure sterility, which would generate a lot of heat during this process, accompanied by ionization and excitation of polymer molecules and API degradation. To minimize the impact of irradiation on API purity, four approaches are proposed. 1. Dry ice is packed with vials containing microspheres for irradiation to reduce temperature hikes. 2. E-beams irradiation at high energy output rate. Compared with gamma ray, E-beams at higher power can significantly reduce the duration of irradiation, thereby lower the risk of impurities formation. However, it is also argued that the high penetrability of E-beams might be easier to cause the denaturation of peptide within microspheres. 3. Co-encapsulated functional excipient as protectant. Protective excipients such as polyols, carbohydrate, pH adjuster can be encapsulated into microspheres together with the API. The introduction of viscous excipients and excipients with functional groups forming bonds with API molecule might provide protection against the harsh conditions created by irradiation. 4. Lyo-protectant. Additives such as buffer, enzyme, protein, and sugar can be added into the PLGA microspheres suspension before lyophilization. During the sublimation process, the interaction might be formed between API and some specific functional bonds of lyo-protectant. And it would prevent the API to be denatured by irradiation ray.