FMEA-Integrated Aseptic Process Simulation for Sterile Ophthalmic Manufacturing

Abstract

Aseptic process simulation (APS), also known as media fill simulation, provides microbiological evidence of an aseptic manufacturing process under representative operating conditions. Integrating prospective Quality Risk Management (QRM) with APS may strengthen the identification and evaluation of contamination risk. An industrial-scale APS study assessed a sterile ophthalmic filling procedure using Soybean Casein Digest Medium (SCDM) in 5 mL LDPE containers under Grade A conditions with a Grade B background. A prospective Failure Mode and Effects Analysis (FMEA) was conducted to identify contamination-related risks and define the controls before the APS. The simulation incorporated routine and non-routine interventions, including equipment adjustments, component replenishment, line disturbances, simulated breakdowns, and a 10-minute power interruption. Growth-Promotion Testing (GPT), sterility testing, physicochemical evaluation, environmental and personnel monitoring, microbiological container closure integrity (CCIT), and post-incubation stasis testing were performed. 9,100 filled units were transferred for inspection and incubation; after 14 days, no microbial growth was detected in any of the 9,100 incubated units. With 9,690 units equivalent received, 482 units equivalent sampled, 96 units equivalent representing media loss, 12 non-integral bottles rejected during filling, and 9,100 filled units, media accountability was reconciled to zero. GPT was satisfactory for Candida albicans, Pseudomonas aeruginosa, and Staphylococcus aureus. Sterility testing showed no growth, environmental and personnel monitoring met predefined criteria, and 20/20 CCIT-challenged containers passed. The integrated findings show the complementary value of prospective FMEA and APS and support microbiological control of the evaluated aseptic ophthalmic filling process under the simulated conditions.