Comparative Leachable Study of Glass Vials to Demonstrate the Impact of Low Fill Volume.

The pharmacopeia method for measuring the chemical durability of parenteral glass packaging is the hydrolytic resistance test in which the vial is filled to 90% of its brimful volume as described, for example, in USP <660>. However, an increasing number of innovative drugs are filled significantly below the nominal volume of the vial. As a consequence, the determined hydrolytic resistance is not representative of the concentrations of leached "glass" elements for low fill volumes. This is attributable to two main factors: Firstly, an increasing ratio of the wetted surface to volume and secondly an increased leaching tendency typically observed with borosilicate glass of the wall near bottom area, especially when standard manufacturing technology is applied.The extent of both contributing effects has been analyzed by determining the amounts of the representative leached "glass" elements, boron, sodium, and silicon, after vial storage for 24 weeks at 40°C with different fill volumes (0.5, 1.0, and 2.0 mL). The vials which have been investigated in this study have a nominal fill volume of 2 mL, were made from Type I class B borosilicate glass (Fiolax®) and from aluminosilicate glass and were filled with either purified water or a 15% KCl solution.The standard conversion process for tubing into vials was used for Fiolax vials (standard quality vials) and for aluminosilicate vials. In addition, an optimized conversion process (delamination controlled technology) was used to create low-fill quality Fiolax vials. The vial quality obtained from the two different converting technologies greatly influenced the concentrations of leached "glass" elements measured, especially when low fill volumes were used. Borosilicate glass containers, because of their chemical inertness, excellent barrier properties, high transparency, and mechanical stability, have been successfully used for decades to package parenteral drug formulations. Nevertheless, Type I glass can be altered over a period of time when in contact with the drug formulation. The result of this interaction is even more pronounced for some new innovative drugs that are delivered to the patient in small dosages significantly below the nominal storage capacity of the glass vials. When the fill volume of the vials is reduced, the contribution of the bottom area to the wetted surface increases, resulting in a higher surface-to-volume ratio. Therefore, the concentrations of leached elements will be increased and this can cause problems for sensitive medical products. This effect is not usually observed with the standard test procedures described in the pharmacopeia because the vials are filled with a high volume to 90% brimful capacity (e.g., as described in USP <660>). In this study, the leachable behaviors of vials made of borosilicate and aluminosilicate glass were evaluated by using medium and low fill volumes with storage for 24 weeks at 40°C. The standard conversion process to manufacture a vial from glass tubing introduces volatile "glass" elements into the vial wall near the bottom area. This mechanism has been described and supported by time-of-flight secondary ion mass spectrometry (TOF-SIMS) measurements of the inner vial surface as reported by Rupertus et al. The diffusion mechanism of volatile components will increase the leaching propensity of the vial, especially for low fill volumes. However, innovative manufacturing techniques are able to avoid the diffusion of volatile elements into the wall near the bottom area. This is achieved by a specific process setup in combination with a suitable monitoring test during vial production, which gives a quantitative measure of the leaching tendency of the wall near the bottom area. Borosilicate glass vials manufactured with this setup (low-fill quality vials) showed a drastic reduction in leachables, especially with low fill volumes. Vials composed of a boron-free glass showed no advantages in terms of leaching behavior when compared with borosilicate glass vials in general.