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Radiation Sterilization Compatibility of Medical Packaging Materials

By Sherwin Shang, Michael T. K. Ling, Stanley P. Westphal, and Lecon Woo
Baxter Healthcare Round Lake , IL 60073 USA Introduction Gamma sterilization is becoming popular in medical device and packaging industry because of convenience and low cost. Concerns of worker exposure to ethylene oxide and temperature limits of medical materials during high steam autoclaving have made gamma sterilization more preferable. This mode of sterilization is a consequence of the high energy electrons released from the interaction of the gamma ray photons with materials. These high energy electrons in turn react with the DNA sequences in the microbiological burden in the devices, and permanently alter their chemical structure to render them innocuous. The high energy electrons, however, can also initiate ionization events in the material being sterilized. It can create peroxy and hydroperoxy free radicals in the presence of oxygen, and start the degradation cascade. This could result in unacceptable color formation, pH shifts and extractables. Furthermore, the degradation could also lead polypropylene (PP) to the wellpublicized catastrophic failures during post radiation shelf life. From application and quality viewpoints, it is thus highly desirable to develop simple and rapid systems to characterize radiation sterilized packaging materials. In this study we have examined some of the widely used medical packaging materials for their gamma compatibility. Different materials degrade via various mechanisms, leading to different modes of failure such as discoloration, excessive pH shifts and high extractables, and catastrophic failures. We need to take them into account in order to gain proper understanding for broad applications. Accordingly, the objective of this study is to develop simple (minimum sample preparation) and very rapid (minutes) techniques to characterize the radiation sterilized packaging material properties. Specifically, oxidative induction time (OIT) and yellowness index (YI) will be used to identify radiation sterilization compatibility. OIT, a method of thermal analysis, is used to measure the total stability of a polymer at a given condition. A more stable plastic has a higher OIT value.

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Experimental and Materials Three techniques are used. It includes ASTM D3895-92 isothermal OIT from Dupont 1090 thermal analyzer with 910 differential scanning calorimetry (DSC) cell. YI follows ASTM D1925 measured by a Hunter colorimeter. Each stabilizer chemical concentration was determined by high performance liquid chromatography (HPLC) from the established calibration systems. The materials studied consist of PP, high density polyethylene (HDPE), and polyvinyl chloride (PVC) with various stabilizer systems. Gamma exposure at 20 and 40 KGy was conducted in a laboratory gamma cell at dose rates of approximately 6 KGy/hr. Results and Discussion PVC thermal stability, measured as OIT in Fig 1, has been reported to exhibit a rather sharp maximum with respect to the concentration of a primary stabilizer, Calcium Zinc stearate at about 0.2 phr (part per hundred) or about 0.13% for the system studied (2). It was also noted that an extremely linear relationship was found for the secondary stabilizer such as epoxidized oil. Combined together, Fig 2 shows that the PVC stability function spanned a 3 dimensional design space. The OIT responses of a PVC formulation at 230o C as a function of the sterilization dose is shown in Fig 3 with a dose rate of about 6 KGy/hr. From the zero dose OIT of about 9 minutes, a steady reduction in total stability was seen. In addition, the slope (rate of OIT decrease) appeared to increase from 20 to 40 KGys, indicating a non-linear response accelerating the degradation reaction at high doses. Fig 3 also indicates that after 40 KGys the formulation loses more than half of the initial total stability. This will limit the maximum dose this particular formulation was capable of sustaining. Radiation also changes polyolefin stability. In a hindered phenol stabilized HDPE film system, the film OIT at 200o C was determined for dose levels of 0, 20 and 40 KGys. Results in Fig 4 clearly indicated significant annihilation of the antioxidants during the course of the sterilization. It was noted that the OIT was nearly flat at 20-40 KGy. This suggests that the antioxidant in question did not provide additional protection when the radiation dose was reduced from 40 to 20 KGy. As Figs 3 and 4 were compared, it was noted that PVC has a slower stability reduction than HDPE when subjected to radiation. In additional to the inherently more stable of PVC over PE, it can be also due to the higher concentration of secondary stabilizer in PVC, which can be about 10%, as shown in Fig 5. This may explain why the medical products made from PVC, seldom encounter catastrophic failure after radiation. Fig 5 also shows that radiation sterilization reduced PVC secondary stabilizer concentration, as measured by HPLC. This in turn reduced material stability as evidenced by OIT. Sterilization by radiation was noted to deplete more secondary stabilizer than the subsequent steam autoclaving and pasteurization combined together. In contrast, catastrophic failures have been reported during PP shelf life storage. Intense

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Page 3 of 11 investigation came to the following consensus (2-4). The long lived free radicals trapped in the crystalline domains migrating toward the crystalline/ amorphous interface combining with available oxygen form peroxy and hydroperoxy radicals that initiated degradation near the interface (3,4). As enough tie molecules between crystallites were cut through the chain scission process, significant reduction of PP's elongation could occur which would lead to catastrophic failures. Since the stabilizer molecules in PP reside primarily in the amorphous phase, its effectiveness to react with primary free radicals preferentially is an indication of the overall post irradiation stability of the material. Accordingly, it is interesting to assess the correlation between OIT and radiation dose based on different suppliers. Fig 6 shows PP from three different suppliers, and their OIT at 200 C at 0, 25 and 50 KGy of doses. It is clearly seen that supplier As formulation, where the OIT vanishes after only 25 KGy, was not as stable, or effective toward gamma radiation as the other two formulations. On the other hand, although PP formulations from suppliers B and C had experienced major reduction of OIT, significant portions remained to protect against further degradations. Fig 7 plots the OIT from three PP suppliers with the phenolic primary anti-oxidant assayed by HPLC. The very good correlation indicated the promise of using this simple procedure as an early screening tool for evaluating PP radiation stability. The stability of a radiation sterilized PP can thus be simply and very rapidly determined by OIT, and the remaining antioxidant level of sterilized PP can be easily obtained by the correlation like Fig 7. Moreover, Fig 7 indicates that the stability of sterilized PP depends on the supplier stabilizer system. In a HDPE system stabilized with hindered phenolic antioxidants, the result of high temperature induction time dependence on antioxidant concentration was established, and shown in Fig 8. The exceptionally linear response of OIT at different temperatures for this system clearly indicates the potential as a simple (minimum sample preparation), and very rapid (minutes) non-specific assay for evaluating HDPE radiation stability. Yellowness Index (YI) can be also used to characterize the material stability. A higher YI suggests more extensively degraded as the same family of materials is compared. When YI of PVC film was plotted with OIT measured at 230o C, Fig 9 shows a very good correlation. Both OIT and YI samples were taken from a 190o C oven heating test at different times. It is noted that as OIT reduced from 9 to 4 minutes, the PVC YI value increased from 20 to 50. The increase in YI can be related to the poly-ene formation in PVC and quinone and hydroquinone formation from phenolic antioxidants due to radiation and thermal exposures. Without quinone and hydroquinone formation in a proper stabilizer system, the increase in PVC color, measured by YI, is the result of a series of conjugated dienes (poly-enes) in PVC molecule chains formed by cationic dehydrohalogenation of PVC. Since the electrons on these conjugated dienes can freely move over the entire length of the conjugated diene, a one dimensional electron well resulted. The length of conjugated dienes can be increased due to ineffective stabilizer protection during radiation sterilization. The energy levels and the absorption spectra of the free electron can thus begin to move from UV toward the visible wavelengths. As the absorption spectra increase in intensity from the short wave length direction, the originally

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Page 4 of 11 clear PVC film starts to appear yellow to dark yellow, orange, red, and finally black as the degradation progresses. In PVC packaging material, a better quality packaging made from a superior stabilizer system is expected to have a higher thermal stability than a standard packaging material. The superior stabilizer system has an extra additive component than the standard stabilizer system. Fig 10 shows that the better quality packaging has a higher OIT for both sterilized and nonsterilized packaging. This is because more effective PVC stabilizer system can minimize both thermal degradation during film extrusion and the subsequent radiation sterilization. Another measure of PVC solution container performance is the turbidity of solution as medial solution stored in sterilized containers. A higher turbidity is generally undesirable due to the concerns of leachables. It was noted in a study that certain formulations that suffered significant loss of OIT have greater tendency in generating turbidity. Evidently, reaction byproducts during radiation sterilization can behave as emulsifiers to solvate extractable components in the PVC. In addition to unacceptable color and solution turbidity formations, excessive pH shifts and high extractables can be observed. These can result in shortened product shelf life storage. By using simple and very rapid techniques developed in this study, a suitable testing for radiation sterilization compatibility of medical packaging material can be developed. Conclusions Simple (minimum sample preparation) and very rapid (minutes) techniques, such as OIT and YI, have been developed in this study to characterize the radiation compatibility of packaging material. These techniques can be used to screen suitable radiation-sterilized packaging materials for the medical industry. References 1. Encyclopedia of Polymer Science and Engineering, "Radiation-Resistant Polymer," Ed., J.I. Kroschwitz, 2nd ed., Vol. 13, p. 687, John-Wiley & Sons, NY (1988) 2. L. Woo, M. T.K. Ling, and E. Chan, "Application of the Oxidative Induction Test to Medical Polymers" Thermochimica Acta, 192, 209(1991) 3. R. J. Rolando, "Radiation Resistant Polypropylene: New Development," J. Plast. Film & Sheeting, 9, (4), 326 (1993) 4. L. Woo, J. Palomo, M.T.K. Ling, E. Chan, C. Sandford, "Shelf-Life Prediction Methods and Applications," Medical Plast. and Biomat., 3, (2), 36 (1996)

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Fig 1: PVC OIT Dependence on CaZn Stearate

Fig 2: 3-Dimensional Schematic of PVC Stability

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Fig 3: Effect of Radiation Dose on PVC Stability

Fig 4: Effect of Radiation Dose on HDPE Stability

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Fig 5: Change of OIT with Secondary Stabilizer Concentration of PVC

Fig 6: Effect of Radiation Dose on PP from Various Supplies

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Fig 7: PP OIT Dependence on Antioxidant Concentration

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Fig 8: HDPE OIT Dependence on Antioxidant Concentration

Fig 9: Correlation of PVC OIT and Color YI

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Ga+ST+Past. = Gamma + Steam autoclaving + Pasteurization Fig 10: Effect of Stabilizer System on PVC Stability

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Page 11 of 11 Back to Abstract

Back to W32-Medical Plastics Characterization

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