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![Structure of EVA multi-layer film (a) and structure of polymers (b). Reproduced from [34] with the permission of European Journal of Pharmaceutical Sciences.](publication/353809096/figure/fig1/AS:1055446907514882@1628649560383/Structure-of-EVA-multi-layer-film-a-and-structure-of-polymers-b-Reproduced-from-34.png)
Structure of EVA multi-layer film (a) and structure of polymers (b). Reproduced from [34] with the permission of European Journal of Pharmaceutical Sciences.
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Chemically and biologically safe storage of solutions for medical uses is a daily concern for industry since decades and it appeared even more dramatic during the last two years of pandemia. Biological safety is readily reached by sterilization using γ-irradiation process. However, such a type of irradiation induces the degradation and the release...
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... thickness of the EVA/EVOH/EVA multilayer film investigated was about 360 µm ( Figure 1). The different layers of the EVA-film contained additives for the stabilization of the film throughout the manufacturing process and throughout its shelf-life [23][24][25][26]. ...
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... formation of the carbonylated compounds (carboxylic acids, ketones, aldehydes) and the degradation of the ester group (Figure 10a) when the γ-dose increases is also observed at the surface of the inner layer of EVA/EVOH/EVA film by XPS [33]. The degradation of ester fonctions is highligthed by the decrease of arrow tagged peaks in Figure 10a from non sterilizes film to 270 kGy-dose irradiated film (decomposition of XPS peak is displayed in Figure 10b). ...
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... formation of the carbonylated compounds (carboxylic acids, ketones, aldehydes) and the degradation of the ester group (Figure 10a) when the γ-dose increases is also observed at the surface of the inner layer of EVA/EVOH/EVA film by XPS [33]. The degradation of ester fonctions is highligthed by the decrease of arrow tagged peaks in Figure 10a from non sterilizes film to 270 kGy-dose irradiated film (decomposition of XPS peak is displayed in Figure 10b). The generation of ketone and aldehyde is also highlighted with the XPS analysis. ...
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... formation of the carbonylated compounds (carboxylic acids, ketones, aldehydes) and the degradation of the ester group (Figure 10a) when the γ-dose increases is also observed at the surface of the inner layer of EVA/EVOH/EVA film by XPS [33]. The degradation of ester fonctions is highligthed by the decrease of arrow tagged peaks in Figure 10a from non sterilizes film to 270 kGy-dose irradiated film (decomposition of XPS peak is displayed in Figure 10b). The generation of ketone and aldehyde is also highlighted with the XPS analysis. ...
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... formation of the carbonylated compounds (carboxylic acids, ketones, aldehydes) and the degradation of the ester group (Figure 10a) when the γ-dose increases is also observed at the surface of the inner layer of EVA/EVOH/EVA film by XPS [33]. The degradation of ester fonctions is highligthed by the decrease of arrow tagged peaks in Figure 10a from non sterilizes film to 270 kGy-dose irradiated film (decomposition of XPS peak is displayed in Figure 10b). ...
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... formation of the carbonylated compounds (carboxylic acids, ketones, aldehydes) and the degradation of the ester group (Figure 10a) when the γ-dose increases is also observed at the surface of the inner layer of EVA/EVOH/EVA film by XPS [33]. The degradation of ester fonctions is highligthed by the decrease of arrow tagged peaks in Figure 10a from non sterilizes film to 270 kGy-dose irradiated film (decomposition of XPS peak is displayed in Figure 10b). The generation of ketone and aldehyde is also highlighted with the XPS analysis. ...
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... formation of the carbonylated compounds (carboxylic acids, ketones, aldehydes) and the degradation of the ester group (Figure 10a) when the γ-dose increases is also observed at the surface of the inner layer of EVA/EVOH/EVA film by XPS [33]. The degradation of ester fonctions is highligthed by the decrease of arrow tagged peaks in Figure 10a from non sterilizes film to 270 kGy-dose irradiated film (decomposition of XPS peak is displayed in Figure 10b). The generation of ketone and aldehyde is also highlighted with the XPS analysis. ...
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... formation of the carbonylated compounds (carboxylic acids, ketones, aldehydes) and the degradation of the ester group (Figure 10a) when the γ-dose increases is also observed at the surface of the inner layer of EVA/EVOH/EVA film by XPS [33]. The degradation of ester fonctions is highligthed by the decrease of arrow tagged peaks in Figure 10a from non sterilizes film to 270 kGy-dose irradiated film (decomposition of XPS peak is displayed in Figure 10b). ...
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... formation of the carbonylated compounds (carboxylic acids, ketones, aldehydes) and the degradation of the ester group (Figure 10a) when the γ-dose increases is also observed at the surface of the inner layer of EVA/EVOH/EVA film by XPS [33]. The degradation of ester fonctions is highligthed by the decrease of arrow tagged peaks in Figure 10a from non sterilizes film to 270 kGy-dose irradiated film (decomposition of XPS peak is displayed in Figure 10b). The generation of ketone and aldehyde is also highlighted with the XPS analysis. ...
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... formation of the carbonylated compounds (carboxylic acids, ketones, aldehydes) and the degradation of the ester group (Figure 10a) when the γ-dose increases is also observed at the surface of the inner layer of EVA/EVOH/EVA film by XPS [33]. The degradation of ester fonctions is highligthed by the decrease of arrow tagged peaks in Figure 10a from non sterilizes film to 270 kGy-dose irradiated film (decomposition of XPS peak is displayed in Figure 10b). The generation of ketone and aldehyde is also highlighted with the XPS analysis. ...
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... thermal analysis by DSC method [34] agrees with permeation experiments. Indeed, the clear changes (T = 15 °C in Figure 11a) in temperatures of melting peak and of melting onsets with γ-irradiation doses highlight the degradation of EVOH layer at 270 ...
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... thermal analysis by DSC method [34] agrees with permeation experiments. Indeed, the clear changes (∆T = 15 • C in Figure 11a) in temperatures of melting peak and of melting onsets with γ-irradiation doses highlight the degradation of EVOH layer at 270 kGy whereas the non significant changes (∆T < 3 • C in Figure 11b) for the same parameters of the EVA layers denote a low level of modifications even up to 270 kGy. Polymers 2021, 13, x FOR PEER REVIEW 12 of 20 kGy whereas the non significant changes (T < 3 °C in Figure 11b) for the same parameters of the EVA layers denote a low level of modifications even up to 270 kGy. ...
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... thermal analysis by DSC method [34] agrees with permeation experiments. Indeed, the clear changes (∆T = 15 • C in Figure 11a) in temperatures of melting peak and of melting onsets with γ-irradiation doses highlight the degradation of EVOH layer at 270 kGy whereas the non significant changes (∆T < 3 • C in Figure 11b) for the same parameters of the EVA layers denote a low level of modifications even up to 270 kGy. Polymers 2021, 13, x FOR PEER REVIEW 12 of 20 kGy whereas the non significant changes (T < 3 °C in Figure 11b) for the same parameters of the EVA layers denote a low level of modifications even up to 270 kGy. ...
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... the clear changes (∆T = 15 • C in Figure 11a) in temperatures of melting peak and of melting onsets with γ-irradiation doses highlight the degradation of EVOH layer at 270 kGy whereas the non significant changes (∆T < 3 • C in Figure 11b) for the same parameters of the EVA layers denote a low level of modifications even up to 270 kGy. Polymers 2021, 13, x FOR PEER REVIEW 12 of 20 kGy whereas the non significant changes (T < 3 °C in Figure 11b) for the same parameters of the EVA layers denote a low level of modifications even up to 270 kGy. ...
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... kinetics observed over the ageing time reveals that the EVA multilayer film after six months of ageing seems in its original state at t0 (i.e., no ageing). This kinetics is displayed with the schematic curves in Figure 12. Thus, the new molecules generated are probably volatile species. ...
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... kinetics observed over the ageing time reveals that the EVA multi-layer film after six months of ageing seems in its original state at t0 (i.e., no ageing). This kinetics is displayed with the schematic curves in Figure 12. Thus, the new molecules generated are probably volatile species. ...
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... kinetics observed over the ageing time reveals that the EVA multilayer film after six months of ageing seems in its original state at t0 (i.e., no ageing). This kinetics is displayed with the schematic curves in Figure 12. Thus, the new molecules generated are probably volatile species. ...
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... product acidity provides valuable information at the molecular level when complementary analysis using titration is performed such as the determination of Total Organic Carbon (TOC), total carboxylic acid, and conductivity [32]. It is possible to determine TOC and to show that it increases with acidity (Figure 13a). TOC can be calculated assuming the generation of formic, acetic, and other C3-C6 acids, titrated by ionic chromatography, and compared with the experimental values (Figure 13b) and it highlights that formic and acetic acids are the main carboxylic acids generated under γ-irradiation. ...
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... is possible to determine TOC and to show that it increases with acidity (Figure 13a). TOC can be calculated assuming the generation of formic, acetic, and other C3-C6 acids, titrated by ionic chromatography, and compared with the experimental values (Figure 13b) and it highlights that formic and acetic acids are the main carboxylic acids generated under γ-irradiation. when complementary analysis using titration is performed such as the determination of Total Organic Carbon (TOC), total carboxylic acid, and conductivity [32]. ...
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... complementary analysis using titration is performed such as the determination of Total Organic Carbon (TOC), total carboxylic acid, and conductivity [32]. It is possible to determine TOC and to show that it increases with acidity (Figure 13a The first acid production pathway (Scheme 5) is due to the γ-irradiation, which generates cation radicals on the carbonyl function. After H-abstraction, these cation radicals give alkyl radicals which promote the generation of carboxylic acids in a cascade of reactions. ...
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... Organic Carbon (TOC), total carboxylic acid, and conductivity [32]. It is possible to determine TOC and to show that it increases with acidity (Figure 13a The first acid production pathway (Scheme 5) is due to the γ-irradiation, which generates cation radicals on the carbonyl function. After H-abstraction, these cation radicals give alkyl radicals which promote the generation of carboxylic acids in a cascade of reactions. ...
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... with a titration curve it is possible to determine three parameters, the maximal concentration of oxidant, the rate of oxidation, and the retardation time, useful to understand the efficiency of the oxidation process as a function of irradiation dose, ageing, and storage time. As an example, Figure 14 displays the change in maximal concentration of methionine sulfoxide (21 days of storage for the solution) depending on dose and ageing. Hence, almost no oxidation is observed after 20 months of ageing whatever the dose. ...
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... , and level of oxidation lower than 3 mM. Then, it is possible to define a desirability function that provides a response surface as displayed in Figure 15 [42]. Hence, for 50 kGy, the maximum of desirability (50%) is reached for long ageing (30 months). ...
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... , and level of oxidation lower than 3 mM. Then, it is possible to define a desirability function that provides a response surface as displayed in Figure 15 [42]. Hence, for 50 kGy, the maximum of desirability (50%) is reached for long ageing (30 months). ...
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... for 50 kGy, the maximum of desirability (50%) is reached for long ageing (30 months). Figure 15. Desirability plots of ageing (months) vs dose (kGy). ...
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... except for the acidity, permeation and oxidation properties, the investigated properties and the material integrity are not significantly altered for the irradiation doses below 50 kGy that are usually applied in industrial sterilization. Thus, the chemical changes observed after γ-irradiation of the EVA multi-layer film are summarized in Figure 16. Deep blue colour is for 100% of desirability (all requirements are fulfilled) and red colour is for 0% of desirability (no requirements fulfilled). ...
Citations
... It has been successfully used in brain malformation clinical cases and in women with stress urinary incontinence (Elzayat & Corcos, 2008). The EVA/ EVOH/EVA multi-layer film is composed of three different types of polymer, affording the generation of several types of radicals for each type of polymer, i.e., PE, which links back to most abundant MP polymer detected in this study (for review of the structure: Gaston et al., 2021). ...
... In this study, a multi-layer film plastic bag comprising of ethylene vinyl acetate (EVA) and ethylene vinyl alcohol (EVOH) copolymers was selected for testing. EVA is a barrier to water and EVOH is a barrier to oxygen and to carbon dioxide 12 . The two polymers also possess excellent durability, low-temperature toughness, and high optical transmission, and thus are good candidates for medical encapsulants 12,13 . ...
... EVA is a barrier to water and EVOH is a barrier to oxygen and to carbon dioxide 12 . The two polymers also possess excellent durability, low-temperature toughness, and high optical transmission, and thus are good candidates for medical encapsulants 12,13 . EVA is also used in the encapsulation of photovoltaic modules, whose degradation behavior under UV radiation is a concern 14 . ...
Many polymer-based medical devices are sterilized by gamma irradiation. To reduce the use of cobalt-60 gamma-ray sources, transition from gamma ray to alternative irradiation technologies was proposed, namely electron beam (e-beam) and X-ray. A major impediment for such a transition is the knowledge gap in material compatibility with the different radiation sources. In this study, multi-layer films consisting of ethylene vinyl acetate (EVA) and ethylene vinyl alcohol (EVOH) components were irradiated to target doses of 30, 45, and 60 kGy by gamma-ray, e-beam, and X-ray sources. Effects of irradiation were evaluated on 12 material properties, and statistical comparisons between gamma irradiation and alternative technologies were conducted using the two one-sided t-test (or “equivalence test”) and classic t-test. Melting temperature and UV absorbance below 300 nm showed dose dependencies, while other investigated properties such as discoloration and mechanical durability did not change with dose up to 60 kGy. Based on these results, there is no material compatibility issue associated with the transition from gamma to e-beam or to X-ray as source of sterilization radiation of the studied multi-layer film.
... 26 In this study, a multi-layer film plastic bag comprising of ethylene vinyl acetate (EVA) and ethylene 27 vinyl alcohol (EVOH) copolymers was selected for testing. EVA is a barrier to water and EVOH is a 28 barrier to oxygen and to carbon dioxide 4 . The two polymers also possess excellent durability, low- 29 temperature toughness, and high optical transmission, and thus are good candidates for medical 30 encapsulants 4,5 . ...
... EVA is a barrier to water and EVOH is a 28 barrier to oxygen and to carbon dioxide 4 . The two polymers also possess excellent durability, low- 29 temperature toughness, and high optical transmission, and thus are good candidates for medical 30 encapsulants 4,5 . EVA is also used in the encapsulation of photovoltaic modules, whose degradation 31 behavior under UV radiation is a concern 6 . ...
Many polymer-based medical devices are sterilized by gamma irradiation. To reduce the use of cobalt-60 gamma-ray sources, transition from gamma ray to alternative irradiation technologies was proposed, namely electron beam (e-beam) and X-ray. A major impediment for such a transition is the knowledge gap in material compatibility with the different radiation sources. In this study, multi-layer films consisting of ethylene vinyl acetate (EVA) and ethylene vinyl alcohol (EVOH) components were irradiated to target doses of 30, 45, and 60 kGy by gamma-ray, e-beam, and X-ray sources. Effects of irradiation were evaluated on 12 material properties, and statistical comparisons between gamma irradiation and alternative technologies were conducted using the two one-sided t-test (or “equivalence test”) and classic t-test. Melting temperature and UV absorbance below 300 nm showed dose dependencies, while other investigated properties such as discoloration and mechanical durability did not change with dose up to 60 kGy. Based on these results, there is no material compatibility issue associated with the transition from gamma to e-beam or to X-ray as source of sterilization radiation of the studied multi-layer film.
... The TOC is suitable for estimating and comparing the sum of all present organic extractables. For the extracts of the tube and film samples, the TOC is mainly composed of small, water-soluble radiolysis products from the irradiation, such as organic acids (Gaston et al., 2021). They are quantitatively equivalent for differently irradiated test samples (percentage difference ≤ 30%). ...
Single-use (SU) devices and assemblies used as manufacturing equipment in the biopharmaceutical industry require comprehensive qualifications. These qualifications include the assessment of compounds released from SU devices in contact with the process fluids, and how these leachable compounds potentially influence process performance, drug product quality, and patient safety. SU suppliers need to provide comprehensive qualification data for several parameters, for both new products and product changes, such as changes in the sterilization process applied to the SU device. The introduction of X-ray irradiation as an alternative to the currently used and established gamma irradiation of SU devices represents a situation where robust data is required to demonstrate equivalency between these two radiation technologies. Here, we present the results of a comprehensive extractables study for three SU components, bags, tubing, and sterilizing grade filters, evaluated after X-ray and gamma-ray irradiation. The selected study conditions were set up to allow a direct comparison of the results from the two sterilization methods, and to allow conclusions to be made on the impact of irradiation type on the polymers and their additives. Orthogonal analytical methods are applied to identify and quantify all compounds present. The data package provided here supports risk assessments for application of irradiated SU equipment in biopharmaceutical manufacturing. The formation of reaction products and the fundamental chemical pathways are discussed and found to be independent of the irradiation type. The results demonstrate the equivalency of both irradiation methods not only for extractables but also for leachables from plastic components used in pharmaceutical and biopharmaceutical manufacturing.
... Therefore, the influence of gamma irradiation on the crystallinity of the EVA/EVOH/EVA (poly ethylene vinylacetate/poly ethylene vinyl alcohol) film is not large enough to be macroscopically detected by FTIR and is not large enough to affect the intended use of that material. By contrast, FTIR analysis combined with principal component analysis (PCA) of the EVA film surface shows a peak at 1714 cm -1 corresponding to the formation of carboxylic acid and a peak at 1739 cm -1 corresponding to the ester group degradation for increasing irradiation dose and overaging time (18). The effect of dose on the formation of carboxylic acid is significant only for doses >50 kGy. ...
... Therefore, the influence of gamma irradiation on the crystallinity of the EVA/EVOH/EVA (poly ethylene vinylacetate/poly ethylene vinyl alcohol) film is not large enough to be macroscopically detected by FTIR and is not large enough to affect the intended use of that material. By contrast, FTIR analysis combined with principal component analysis (PCA) of the EVA film surface shows a peak at 1714 cm -1 corresponding to the formation of carboxylic acid and a peak at 1739 cm -1 corresponding to the ester group degradation for increasing irradiation dose and overaging time (18). The effect of dose on the formation of carboxylic acid is significant only for doses >50 kGy. ...
Methionine oxidation is used as a proxy to model the gamma radiation induced changes in single-use bags. These changes can be the formation of acids, radicals and hydroperoxides due to the irradiation of the multilayer film the single use bag is made from. Biopharmaceutical multilayer polyethylene bags irradiated from 0 to 260 kGy and aged from 0 to 36 months were filled with a methionine solution to follow the oxidation of methionine. Methionine sulfoxide was measured using high performance liquid chromatography after 21 days of storage. The maximum methionine sulfoxide concentration detected after 21 days of storage was analyzed through a design of experiments. The results to the design of experiments were considered to obtain the desirability domain for the optimization of the conditions of use for the single-use bags, limiting the oxidation of methionine as well as the release of reactive species thereof.
