AComDim applied to evaluate gamma irradiation impact on multilayer PE based films

The use of single-use systems is becoming increasingly common in the biopharmaceutical and biotechnology industries. These systems are manufactured from polymers such as polyethylene (PE) and ethylene vinyl acetate (EVA). For their future applications, these devices are sterilized by γ-irradiation with a dose between 25 and 45kGy. C. Artandi and W.V. Winkle[i] determined that 25kGy is the dose to be at 40% above the minimum needed to kill the most resistant microorganisms. The purpose of this study is to understand what happens on the surface of polymers after γ-sterilization. Optical spectroscopy are of great interest for chemical analysis and are used to obtain information on the composition of materials, such as polymers. The Fourier Transform Infrared (FTIR) spectroscopy provides information on the fundamental vibrations of the molecules using an excitation in the visible. The surface of films is analyzed after being sterilized with different radiation doses and after a natural ageing of few months to check their composition and stability by FTIR spectroscopy. As the number of data is important, the use of chemometric methods, like Principal Component Analysis (PCA) and AComDim (ANOVA Common Dimensions), has many advantages, such as identification of shift and intensity modification, detection and highlighting of the influential factors and interactions between several elements (γ-doses, aging, and film batches)

Identification of antioxidant by-products based on their specific chemistry and their potential detection during SUS extractable study

Single-use films in biopharmaceutical and biotechnology industries are mainly made from polymers such as PE, EVA and EVOH. Depending upon the environmental aggressiveness during various stages of the polymer lifetime, additives are added to protect them such as substituted hindered phenols acting as antioxidants, melt (processing) stabilizers, and to some extent as photo-antioxidants. Ionizing radiation effects on polymers have been widely investigated. They consist mainly of free radicals production. These free radicals can in turn lead to degradation and or crosslinking phenomena (release of gases, discoloration, changes in mechanical properties and gas permeability, degradation and leaching of polymer additives into solvents, etc.) whose extent depends on many factors. In contrast, there is little information on the effect of ionizing radiation on the additive package properties used in multilayer packaging films. A specific influence on chemical transformations of phenols is induced as well. Strong discoloration of the polymer stabilized with phenolic antioxidants originates for instance mainly from the reaction products of the stabilizers. The color development can be attributed to the formation of conjugated diene compounds, arising as a consequence of trapping of radicals by phenolics. The discoloration depends on the structure and concentration of the phenolic transformation products. As a result of the described complexity, a huge variety of potential extractable compounds can be expected from antioxidants. This work focuses of highlighting the degradation products we may expect from the thermal and radiative degradation of the primary and secondary anti-oxidants and to address complexity of identifying properly the by-products one may detect in extractable study applied to pharmaceutical single use products

pH evolution in solution after contact with multilayer films after different g- irradiation doses and thus reconciliation of pH and TOC with carboxylic acids detected by ion chromatography

For a number of various uses (storage, mixing, freezing, transportation, formulation, and filling) biopharmaceutical solutions are stored in sterile single-use plastic bags. Material transfers can then occur between containers and contents. These migrations, of different types, depend on the physicochemical characteristics of the material (composition, pH, solubility, viscosity, molecular weight, etc.), the nature of the product (solid, semi-solid and liquid) and the conditions of the material utilization. In the case of single-use polymers, γ-irradiation sterilization of the polymer is often carried out. The interactions could be therefore influenced by the dose and the contact time between the container and the contents. γ-sterilization of single-use systems initiates chemical reactions and complex modifications inside the plastic material, In this study, γ-irradiation doses investigated are up to 270 kGy in order to emphazise the γ-irradiation effect and to better investigate the modifications of commercial PE(Polyethylene)/EVOH(Ethylene Vinyl Alcohol)/PE-film and commercial EVA(Ethylene Vinyl Acetate)/EVOH/EVA film. This study is a part of a global investigation on γ-irradiation on multilayer films Non-specific (TOC, pH, conductivity) or specific (e.g. chromatographic, spectroscopic, gravimetric) analytical methods can be used. several approaches were used to study the impact of γ-irradiation on multilayer films, as ion chromatography to detect and quantify the ionic species, and as pH and conductivity measurements to observe the consequences of the chemical modifications.. There are few references available on the leaching of carboxylic acid species impacting aqueous solutions used in biopharmaceutical applications in contact with plastic single-use systems [[i]]. Stability studies under accelerated or real-time degradation conditions make it possible to define the shelf life and storage conditions in order to guarantee the quality of the product. The aim of the study is to identify and quantify the acid compounds that can be released from the container under normal conditions of use of the materials: the extractables. [[1]] D. Jenke, D and V.J. Barge. Factors affecting the release of extractable acetic acid from multi-layered plastic films containing ethylene vinyl acetate (EVA) and polyethylene (PE) layers. Pharm Outsourcing. 15 (2014) 56-59

Influence of γ-irradiated biopharmaceutical films

Preventing cross-contamination, saving costs and increasing configuration flexibility make the adoption of single-use technologies very attractive for the biopharmaceutical industry. The integrity and the security of bags are due to appropriate flexible and barrier polymeric materials, such as polyethylene (PE) or ethylene vinyl acetate (EVA) and polyethylene-co-vinyl alcohol (EVOH), which are barrier to water vapor and oxygen, respectively. Conventional stainless steel tanks are sterilized by steam sterilization by the end-users, whereas plastic containers are sterilized by gamma-irradiation before delivery. The major advantage of radio-sterilization is the penetration power of the γ-radiation. It is known that γ -sterilization of polyolefin based polymer leads to alterations of the material: changes in the additives or potential damage to the polymer, as reported in the literature. Irradiation of polymeric materials has been proven to initiate radiation chemical reactions inside the polymeric material, leading to either an increase or a decrease in the polymer molecular weight. The effects of γ-irradiation on polymers are well known whereas the effects of γ-irradiation on multilayer films have been little investigated. In the case of multilayer films, the acidity of the stored solution increased after gamma irradiation for instance. In another case oxidation of the solution occurred. Such observations denote the presence of acidic and oxidant compounds, which are issued either from modification of surface of the film or from the migration of by-products from core to surface. A global investigation on γ-irradiation on multilayer films is performed to investigate the γ-irradiation based modifications on PE(Polyethylene)/EVOH(Ethylene Vinyl Alcohol)/PE film and EVA(Ethylene Vinyl Acetate)/EVOH/EVA film to assess the multilayer film robustness. Several approaches could be used to study the impact of γ-irradiation on multilayer films, as ESR (Electron Spin Resonance) to observe the radicals formation, ATR-FTIR (Attenuated Total Reflection-Fourier Transform Infrared) and Raman spectroscopies to observe the structural modifications, the measurement of yellowing, the measurement of O2 transmission rate (O2TR) and water vapor transmission rate (WVTR), the measurement of pH to follow the acidity change of solution contained in the bag and the mechanical test to evaluate the toughness of film. Due to the number of data recorded, chemometric methods, such as Principal Component Analysis (PCA), are applied to enhance the weak variations brought to the γ-irradiation of the multilayer films in the different data sets. Results show that films undergo modifications at microscopic level and that they are not altered from macroscopic and application viewpoints. Results are equivalent from batch to batch assuring then a reproducibility of the films behavior for their integration in single-use systems

Study of mechanical behavior on single use bags welding under gamma irradiation

Since a long time, biopharmaceutical industry utilizes more and more single use plastic bags due to its very easy use (long shelf-lives, mechanical properties), preparation, and storage properties (oxygen and water barriers). These plastic bags are composed of two welded multilayer polymer films. To ensure the function of the closure and the non-contamination from the external environment, welding must answer to several parameters according to norm (“ISO 15747,” 2018) and standard (F02 Committee, n.d.). In this present study, the behavior of weldings on Ethylene Vinyl Acetate (EVA) single use bags under gamma irradiation have been studied. Mechanical tests have been performed at several gamma irradiation doses (from 0 kGy to 270 kGy) and at different location of the bag (Figure 1). The first objective is to study the impact of gamma irradiation dose on the welding mechanical tensile behavior. The second objective is to evaluate the impact of the welding location on the welding tensile properties. Each tensile curve (Figure 2) has been decomposed in 6 characteristic points which were evaluated with Principal Component Analysis (PCA): Ultimate Tensile strength at break (UTS), Ultimate elongation or elongation at break, 1st Yield-Strength (Y1 Strength), 1st Yield-Strain (Y1 Strain), 2nd Yield-Strength (Y2 Strength), 2nd Yield-Strain (Y2 Strain). The study showed that weldings are never impacted during tensile testing: this evaluation reveals that in fine the film cracks before the welding modification. Its function of closure and bag content preservation from external environment is fully achieved whatever the gamma irradiation dose and the welding location. Only the multilayer film on both sides of the welding is altered after 100% elongation strain. The EVA bag showed no degradation up to 115 kGy whereas they become to be altered at 270 kGy. The welding location on EVA bag showed different film mechanical behavior correlated to the polymer film extrusion process orientation. Please click Additional Files below to see the full abstract

Implementing X-ray for single use systems sterilization: Current status

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Implementing X-ray for single use systems sterilization

Sterilization/decontamination by gamma irradiation is a standardized process for some medical devices, drugs and in the food field and has many advantages due to its significantly low toxicity. Many worldwide industrial sites offer gamma irradiation as a means of sterilization, and in the last decade, new irradiation modality such as X-rays or electron-beam raises. These methods make also possible the sterilization of products without significant heating and to handle them directly in their final packaging, to overcome the challenges encountered e.g., due to sterilization capacity constraints. All irradiation modalities are reliable and reproducible processes and ensure sterility over time by avoiding any possible risk of contamination. It will thus reflect on post-pandemic world solutions to build capacity with high flexibility, while looking forward to anticipating future increase in sterilization demand without negative implications/repercussions in all industries where sterilization is needed. Unfortunately, these radiation processing also present disadvantages of inducing modifications for exposed materials. Some factors could affect the observed changes, such as their chemical composition, additives, or the presence of oxygen in the environment. X-ray industrial units are beginning to emerge, and the question of a comparative study between the effects of different types of radiation and their health impact on the materials/products studied arises. This current lack of data represents a hurdle for medical device and biopharmaceutical manufacturers desiring to transition from gamma-ray sterilization modalities to X-ray or electron-beam. Communicating to the industry our approach and polymer effects results can support medical device and biopharmaceutical manufacturers to perform their own risk assessment when piloting the transition to alternative irradiation modalities. In an effort to help fill these data gaps previously enounced, physicochemical testing, mechanical testing, extractables testing, etc. will be performed on products including their polymer components previously irradiated by the different irradiation modalities (gamma and X-ray). Highlights: - Support biomanufacturers to perform their own risk assessment when piloting the supplementing of alternative irradiation modalities to ensure business continuity during sterilization processes - Comparative study between the effects at materials/components & sub-assemblies/products of different types of ionizing radiations - Understanding the parameters inducing modifications for exposed SUS to irradiation - Physicochemical testing, mechanical testing, extractables testing, functional testing, activation, etc. will be performed on products and their polymer components previously irradiated (gamma and X-ray)

How intramolecular hydrogen bonding (IHB) controls the C-ON bond homolysis in alkoxyamines

International audienceRecent amazing results (Nkolo et al., Org. Biomol. Chem., 2017, 6167) on the effect of solvents and polarity on the C-ON bond homolysis rate constants kd of alkoxyamine R1R2NOR3 led us to re-investigate the antagonistic effect of intramolecular hydrogen-bonding (IHB) on kd. Here, IHB is investigated both in the nitroxyl fragment R1R2NO and in the alkyl fragment R-3, as well as between fragments, that is, the donating group on the alkyl fragment and the accepting group on the nitroxyl fragment, and conversely. It appears that IHB between fragments (inter IHB) strikingly decreases the homolysis rate constant kd, whereas IHB within the fragment (intra IHB) moderately increases kd. For one alkoxyamine, the simultaneous occurrence of IHB within the nitroxyl fragment and between fragments is reported. The protonation effect is weaker in the presence than in the absence of IHB. A moderate solvent effect is also observed