Conservative Exposure Predictions for Rapid Risk Assessment of Phase-Separated Additives in Medical Device Polymers

Abstract

A novel approach for rapid risk assessment of targeted leachables in medical device polymers is proposed and validated. Risk evaluation involves understanding the potential of these additives to migrate out of the polymer, and comparing their exposure to a toxicological threshold value. In this study, we propose that a simple diffusive transport model can be used to provide conservative exposure estimates for phase separated color additives in device polymers. This model has been illustrated using a representative phthalocyanine color additive (manganese phthalocyanine, MnPC) and polymer (PEBAX 2533) system. Sorption experiments of MnPC into PEBAX were conducted in order to experimentally determine the diffusion coefficient, D = (1.6 ± 0.5) × 10 cm/s, and matrix solubility limit, C = 0.089 wt.%, and model predicted exposure values were validated by extraction experiments. Exposure values for the color additive were compared to a toxicological threshold for a sample risk assessment. Results from this study indicate that a diffusion model-based approach to predict exposure has considerable potential for use as a rapid, screening-level tool to assess the risk of color additives and other small molecule additives in medical device polymers.

Relations Between Dynamic Localization and Solute Diffusion in Polymers

“…To address these challenges, recent work has been aimed at developing physics-based transport models to rapidly provide more clinically relevant exposure estimates. ,− These models can be used to predict the release rate of leachable chemicals from device materials over time by modeling physical processes like diffusion, fluid flow, and chemical reactions. Each of these processes requires system-specific material parameters to be established, such as the diffusivity D of a solute in a polymer when modeling diffusive flux.…”

Advances in predicting patient exposure to medical device leachables

“…For these larger molecules, sorption experiments must be conducted with the polymer exposed to a liquid‐phase solution with dissolved leachable. For example, liquid sorption experiments have been used to characterize D for various colour additives in device‐relevant polymers (Chandrasekar, Janes, Forrey, et al, 2018; Chandrasekar, Janes, Saylor, et al, 2018). While monitoring bulk mass uptake into a neat polymer is the most straightforward method to assess D , other techniques such as concentration profiling (Roe et al, 1974; Saylor et al, 2018), diffusion cells (Morrissey & Vesely, 2000) and labelling techniques (Jokš, 1987) are also frequently used.…”

“…% crystallinity and T g ), experimentally establishing D for a specific system can take a significant period of time. For example, a 32‐week liquid sorption experiment was required to characterize D for a colour additive, manganese phthalocyanine, in PEBAX 4033 (Chandrasekar, Janes, Saylor, et al, 2018).…”

“…Thus, leaching is slowed in proportion to S . While initially developed to predict drug release from drug delivery systems, Equation has been shown to accurately describe leaching for other additives found in device polymers (Chandrasekar, Janes, Forrey, et al, 2018; Chandrasekar, Janes, Saylor, et al, 2018). Fortunately, S can be derived directly from sorption experiments, provided the polymer sample is immersed in a saturated solution of the leachable.…”

The Ubiquitous Issue of Cross-Mass Transfer: Applications to Single-Use Systems

“…It offers a robust methodology to mitigate the risk of contamination regardless of the considered materials, substances, and routes of accretion. Despite calls for unified approaches [32,33,34], migration modeling is comparatively less developed for medical applications [35,36,37]. The needs have been revived in recent years, with the extending concern associated with endocrine-disrupting chemicals [38,39,40,41] and low-dose effects [42].…”