Pharmaceutical compounding and storage of faricimab in a syringe for intravitreal injection do not impair stability and bi-specific binding properties.

BACKGROUND: Intravitreal injection (IVI) of antibody biologics is a key treatment approach in ophthalmology. Pharmaceutical compounding and storage of prefilled syringes for IVI must take place without impairing the structure and function of the biologics. This study investigated the effect of withdrawing and storing the therapeutic antibody faricimab (Vabysmo, Roche, Basel, Switzerland) in the Zero Residual silicone oil-free, 0.2-mL syringe (SJJ Solutions, The Hague, the Netherlands). METHODS: To assess the effect of syringe withdrawal on faricimab, we compared samples from syringes prepared at day 0 with samples taken directly from faricimab vials. To assess the effect of syringe storage on faricimab, we kept prefilled syringes in the dark at 4 oC for 7, 14, or 37 days and compared samples from these syringes with day 0. We measured protein concentration (with spectrophotometry), stability and integrity (with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), size-exclusion chromatography (SEC), and melting temperature (Tm)), as well as binding of faricimab to its cognate antigens: vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (Ang-2) (with enzyme-linked immunosorbent assay (ELISA)). RESULTS: Faricimab migrated in line with its expected molecular mass under both reducing and non-reducing conditions for all time points when analyzed with SDS-PAGE, without any sign of degradation products or aggregation. The SEC elution profiles were identical for all time points. There were slight variations in Tm for different time points compared to day 0 but without consistent relationship with storage time. ELISA did not detect differences in VEGF-A or Ang-2 binding between time points, and faricimab did not bind the neonatal Fc receptor. CONCLUSIONS: Withdrawal and storage of faricimab in syringes for up to day 37 did not impair the structure and bi-specific binding properties of the therapeutic antibody.

Does Pharmaceutical Compounding of Vascular Endothelial Growth Factor Inhibitors for Intravitreal Use Alter the Risk of Post-injection Endophthalmitis?

PURPOSE: To investigate the safety of pharmaceutically compounded syringes for intravitreal administration of anti-vascular endothelial growth factor (anti-VEGF) drugs. METHODS: Single center, retrospective chart review. From 2015 to 2019, Oslo University Hospital, Norway gradually implemented pharmaceutical compounding and splitting of bevacizumab, ranibizumab, and aflibercept vials into multiple prefilled syringes for intravitreal use. Medical records of all post-injection endophthalmitis (PIE) cases in this 5-year period were reviewed. The incidences of PIE associated with compounded and clinician-withdrawn syringes were compared. RESULTS: In 5 years, the total number of anti-VEGF injections was 112,926; 68,150 procedures (60%) utilized compounded syringes, and 44,776 procedures (40%) utilized clinician-withdrawn syringes. A total of 11 PIE cases were identified (incidence 0.10 per 1000; 95% CI 0.05-0.17). Five PIE cases were associated with compounded syringes (incidence 0.07 per 1000; 95% CI 0.03-0.17); 3 of these were culture positive. Six PIE cases were associated with clinician-withdrawn syringes (incidence 0.13 per 1000; 95% CI 0.06-0.29); 2 of these were culture positive. The relative risk of PIE following procedures utilizing compounded versus clinician-withdrawn syringes was 0.55 (95% CI 0.17-1.79; p = 0.32). CONCLUSION: Use of compounded anti-VEGF drugs in a large clinical setting was not associated with an altered risk of PIE. The finding adds to the evidence that splitting of vials into prefilled syringes for intravitreal injections is safe, provided that an appropriate pharmaceutical compounding procedure is strictly followed.

Cluster of symptomatic silicone oil droplets following intravitreal injections: a 1-year observational study.

OBJECTIVE: To describe a cluster of symptomatic intravitreal silicone oil (SiO) droplets following intravitreal injections (IVIs) and assess the effect of switching to a SiO-free syringe. METHODS AND ANALYSIS: Observational quality registry study of patients receiving IVI at a large Norwegian ophthalmology centre between April 2018 (start of cluster) and November 2019 (1 year after switching to SiO-free syringes). At onset, anti-vascular endothelial growth factor drugs were administered using SiO-containing insulin syringes. From November 2018, SiO-free syringes were implemented. Spontaneously reported symptomatic SiO cases were confirmed by slit-lamp examination. A follow-up interview was performed after 1 year, assessing visual complaints. The prevalence of non-symptomatic cases was assessed in a sample of 50 eyes from 50 consecutive IVI patients. RESULTS: Among 13 429 IVIs, 50 eyes of 46 patients (29 women) with symptomatic intravitreal SiO droplets were identified. Forty-one patients reported floaters at regular appointments, whereas five patients contacted the department regarding symptoms between scheduled appointments. After 1 year, 34 patients (79%) still experienced floaters, 21 (49%) reported reduced symptoms and 3 (7%) reported worsened symptoms. Eighteen patients (42%) reported being bothered, and eight (18.6%) reported that their lives were negatively affected by the floaters. Among 50 non-symptomatic eyes that had received IVI during the same period, intravitreal SiO was found in 34 (68%). No cases of symptomatic intravitreal SiO droplets were identified after switching to SiO-free syringes. CONCLUSION: Symptomatic intravitreal SiO following IVI can cause significant and prolonged distress for affected patients. It can be avoided by using SiO-free syringes.

A new method for pharmaceutical compounding and storage of anti-VEGF biologics for intravitreal use in silicone oil-free prefilled plastic syringes.

Intravitreal injections of antibody-based biologics targeting vascular endothelial growth factor (VEGF) are highly effective and have markedly decreased the risk of visual impairment associated with prevalent retinal diseases, such as neovascular age-related macular degeneration and diabetes macular oedema. The diseases are chronic in their nature, and most patients need long-term therapy to suppress disease activity. We previously reported a compounding method for repackaging and storage of aflibercept (Eylea), a commonly used anti-VEGF biologic, in silicone oil-coated plastic syringes without compromising drug stability or activity. In addition to improving safety and time spent per patient, compounding of anti-VEGF biologics enables single-dose vials to be split into multiple syringes, thereby considerably reducing waste and drug expenses. However, symptomatic silicone oil droplets may deposit in the eye's vitreous body after repetitive injections. To fully avoid this complication, we here report on a novel pharmaceutical compounding method using silicone oil-free syringes and a 33 G × 9 mm Low Dead Space Needle hub injection needle. We evaluate the method for three anti-VEGF biologics commonly used in ophthalmology: aflibercept, ranibizumab (Lucentis) and bevacizumab (Avastin). Our results show that compounding and storage for one week does not compromise the functional activity of the biologics and allows for safe and cost-effective compounding of anti-VEGF biologics for intravitreal injections in prefilled silicone oil-free syringes.

Pharmaceutical compounding of aflibercept in prefilled syringes does not affect structural integrity, stability or VEGF and Fc binding properties.

Macular edema due to neovascular age-related macular degeneration, diabetes or retinal vein occlusion can cause central vision loss. Intravitreal treatment with antibody-based biopharmaceutical compounds designed to neutralize vascular endothelial growth factor (VEGF) has proven to be an efficient strategy to ameliorate macular edema and restore visual acuity. At the same time, the use of anti-VEGF drugs places an economic burden on the health care system; the drugs are expensive, and repeated injections are usually required to maintain the therapeutic effect. Thus, there is an unmet need for more cost-effective procedures. We here describe how the most recently approved anti-VEGF drug, aflibercept, can be compounded into prefilled sterile syringes and stored for up to 4 weeks without compromising its quality, stability or functional properties, including VEGF and neonatal Fc receptor (FcRn) binding. The novel compounding method for repackaging of aflibercept in sterile plastic syringes can greatly reduce both cost and time spent per patient in the injection room.