Zoledronic Acid 6ml Vial Shelf Life Study

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Abstract
Bisphosphonates (e.g. zoledronic acid) are widely used drugs designed to inhibit bone resorption in cases of osteoporosis and other bone diseases. Administered as an intravenous infusion, bisphosphonate solutions present unique challenges in packaging as they react with di- and polyvalent cations present in current glass packaging products. The result has a potential for chelation of residual metal ions, which are also present in borosilicate glass, and metal chelation is known to result in undesirable particulate formation. SiO2 Medical Products, Inc. filed a Type II variation of a European national marketing authorization for zoledronic acid in silica-coated 6ml Cyclic Olefin Polymer (COP) vials to allow European authorities the ability to evaluate SiO2™ primary containers and coating. A leachables study (6 months) was performed to showcase the advantages of silica-coated COP vials (6ml) for zoledronic acid (4mg/5ml) packaging under realtime aging and accelerated aging.

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Study
With an objective to determine leachable compounds present in zoledronic acid, 6ml COP vials were used:

vials coated with SiO2™ silica coating, filled with 5ml contact solution and sealed with fluorinated bromobutyl stopper. Another set of blank, inert glass vials filled with blank solution was also generated.

These sets of samples sent to Toxicon Europe for study under aging conditions (6 months real time (25C/60% RH) and accelerated aging (40C/75% RH).

Targeted leachables for this study include: monomer remainders, polymer degradation products, residual solvents, antioxidants, plasticizers, lubricants, metal elements, formate and acetate.

Analytical Methods (after extraction):

• Volatile organic compounds (HS-GC/MS): Headspace-gas chromatography/mass spectroscopy

• Semi-volatile organic compounds (GC/MS): Gas chromatography/mass spectroscopy

• Non-volatile organic compounds (HRAM-UPLC/MS): High resolution accurate mass-ultra performance liquid chromatography/mass spectroscopy)

• Elements (ICP-OES): Inductively-coupled plasma/optical emission spectroscopy

• Anions (IC): Ion chromatography

Results
Leachable Results (6 months real-time):

• Volatile organic compounds: < AET

• Semi-volatile organic compounds: < AET

• Non-volatile organic compounds: < AET

• Elemental compounds: < limit of quantification

• Anions (IC): trace amounts of formate and acetate

NOTE: For volatile, semi-and non-volatile compounds no compound identification available because amounts are below AET.

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SiO2™ Coating System
SiO2’s engineered, silicon-based barrier coating system is manufactured from monomer gas in a plasma enhanced chemical vapor deposition process. This coating system is applied to the interior surface of the container and contains no metals that can leach into the drug and cause delamination in borosilicate glass containers.

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Conclusion
The results exhibit that SiO2™ vials are viable and the appropriate primary container to utilize for the zoledronic acid drug product. This project was undertaken by SiO2 to provide the fastest regulatory approach for the SiO2™ product and coating technology to be evaluated in Europe. The results support a conclusion that pharmaceutical partners may reduce risk by filing for market authorization in Europe with their drug product in SiO2™ primary containers.

www.sio2med.com



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