Polimer Bazlı Tıbbı̇ Malzemelerden Nitrozamı̇nler ve Nı̇trozlanabı̇len Maddeler için Analı̇z Metodunun Geliştirilmesi

Abstract

Extractable and leachable substance determination and corresponding toxicological risk assessment strategy is the essential part of the biological evaluation of the medical devices. One of the main obligations for placing medical devices on the market is to have undergone a biocompatibility assessment. Therefore, the appropriateness of biological evaluation of medical devices depends on the robustness and accurateness of the extractable and leachable studies. In this study, a targeted analysis approach for the determination of N-nitrosamines and N-nitrosatable substances was established for medical devices made of rubber and elastomer, which are prone to leaching these substances. Sampling methodologies were examined considering the approaches in EN ISO 10993-12 and EN 12868 for nitrosatable substances. Appropriate GC-MS parameters were established for the qualitative and quantitative analysis of NDPA, NMOR, NPYR, NPIP, NDiBA, NDBzA and NDiNA using screening (SCAN) and selected ion monitoring (SIM) modes, respectively. Linearity, LOD-LOQ, accuracy ande precision studies were performed for the established GC-MS method and measurement uncertainty was calculated based on these studies and method validation was thus performed.

The results show that the calibration curves are linear within the 10-100 µg/L concentration range with a minimum r2 value of 0.9965. The LOD and LOQ values are in the range 1,6-19 µg/L and 5,5-56,4 µg/L for all substances, respectively. For the validation studies, concentraitons of 20 µg/L, 60 µg/L and 100 µg/L were selected and repeatability and reproducibility conditions were achieved with low relative standard deviation values. For six nitrosamine substances, the recovery rates at each concentration point are within the standard's prescribed limits of 95±30%. Only at 20 µg/L point, the recovery value for NDiNA was %131, which did not meet the acceptance criteria. Within the scope of this thesis, the method developed for the analysis of N-nitrosamines and N-nitrosatable substances in polymeric medical devices was validated and determined to be an efficient method when compared with the relevant regulations, standards and literature.