Effect of external surface terminal sterilization of prefilled syringes (PFS) with ethylene oxide (EO) on the concentration and stability of ranibizumab (RBZ)

Abstract

Purpose : The RBZ 0.3 mg PFS eliminates the need for drug transfer from vial to syringe. External surface sterilization of the PFS for intravitreal use requires the removal of potential contaminants to meet the required sterility assurance level while protecting drug integrity. Terminal sterilization of the external surface of the PFS with EO is based on US Food and Drug Administration guidance. We assessed the effect of external surface terminal EO sterilization on drug quality.

Methods : The external surface of the RBZ 0.3 mg PFS was sterilized using EO gas to achieve a minimum sterility assurance level (SAL) of 10^–6 (probability of 1 in 1,000,000 of finding a nonsterile unit). The sterilization process was validated using the biological indicator, Bacillus atrophaeus. EO and ethylene chlorohydrin (ECH) residuals were determined in the finished PFS by gas chromatography assay. RBZ in presterilized and EO-sterilized PFS batches was qualitatively and quantitatively assessed using high performance liquid chromatography (HPLC), capillary electrophoresis (CE), and potency assays. RBZ stability in the finished PFS stored at 2°C−8°C (regular storage for ≤3 years) and 30°C/65% relative humidity (RH) (stressed conditions for ≤6 months) was evaluated by HPLC assays and standard tests.

Results : External surface terminal sterilization of PFS with EO had no negative impact on RBZ potency and stability. EO and ECH residuals in the finished PFS were below accepted limits (≤1 ppm EO and 50 ppm ECH). Qualitative and quantitative assessment of RBZ in pre-sterilized and EO-sterilized PFS batches using HPLC and CE assays at the stressed condition of 30^οC/65% RH showed comparable changes relative to the initial time point, which suggests equivalent acceleration of drug degradation. Furthermore, RBZ remained stable when stored under the regular storage condition at 2-8^οC for up to 3 years.

Conclusions : External surface terminal sterilization of the PFS with EO, a unique feature of the RBZ PFS, provides further assurance of safety and sterility to the patient and physician. This process had no negative impact on RBZ quality, concentration, and stability under regular storage conditions. Advantages of the sterile PFS include ease of use, time savings and minimal dosing errors.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.