In-Depth Validation of Closed-Vial Technology - The authors describe a validation master plan for closed-vial filling technology. - BioPharm International


In-Depth Validation of Closed-Vial Technology
The authors describe a validation master plan for closed-vial filling technology.

BioPharm International
Volume 25, Issue 9, pp. 30-42

Low temperature storage

Many of the new pharmaceutical drugs belong to the biological class. These products are often sensitive to heat and show lack of stability even at 2–8 C (for example, recombinant viruses and cell therapies). One option is to store them frozen at –20 C, at –70 to –80 C or even in liquid nitrogen (in vapor or submerged inside, i.e., at –196C).

Some issues are reported with glass vials when stored at very low temperature, such as small cracks —ranging up to complete breakage—and loss of closure integrity caused by differential retraction of the stopper regarding the glass vial neck. Loss of integrity can lead to contamination risk, loss of sublimated water, or severe acidification when stored in dry ice.

To assess the suitability of the vial for low temperature storage, WFI-filled vials were stored as long as one year at –20C, –80C, or inside liquid nitrogen. The outcome is that none have shown any visual defect, loss of closure integrity, or loss of water.

To confirm the vial integrity at very low temperature, vials were filled with 100% oxygen and laser-resealed before being immersed in liquid nitrogen. Some unsealed vials were equipped with a small catheter in the stopper as positive samples. After 11 days of storage in these conditions, the oxygen content remained at 100% in resealed vials, whereas it decreased to about 60% in positive vials. This result showed that nitrogen did not enter the resealed vials, thus demonstrating the maintenance of the tightness of the closure.

These tests demonstrate that the closed vial, because of its resistant COC and effective closure assembly, is suitable for long-term storage in extreme conditions of low temperature.

Resistance to breakage

COC is known to be resistant to damage, and resistance to breakage was assessed in two different conditions: by drop test, to assess risk of cracks due to shock, and by freeze-thawing to assess resistance to the expansion of frozen liquids.

Figure 2: Damage to 10-mL closed vials (blue line) and 10R glass vials (red line) when dropped from different heights. Vials were dropped once from each height, starting from the lowest, until damaged or broken.
To quantify resistance to shock and to compare it with that of glass vials, a drop test procedure from different fixed heights to a concrete floor was set up. The percentage of intact and nonleaking vials was recorded for each height. The results showed that for the two tested sizes (1-mL and 10-mL vials), the closed vial is significantly more resistant than the equivalent glass vial (2R and 10R vials). For example, for the 10 mL vial size, 50% of glass vials are broken when falling from table height (75 cm) whereas closed vials can stand up to above 2 meters before seeing the first damage (see Figure 2).

To assess resistance to product expansion, a freezing-thawing test at –80 C was conducted with vials filled with 15% mannitol, which is known to expand significantly during freeze-thawing. This test was performed according to a test reported by Jiang et al. who recorded glass vial breakage when frozen with this solution inside (7). Jian et al. observed that glass vial breakage depends on the filled volume and on the vial size. Jian et al. recorded 100% breakage for 20-mL glass vials and 50–60% breakage with 5- and 10-mL glass vials when filled at half of nominal volume. When this test has been performed according to the same procedure, no broken closed vial was observed with 5-, 10- and 20-mL size. The test was also performed with closed vial filled at full nominal volume and again, no breakage was reported.

This test showed that not only is COC resistant to shocks but that it is also able to tolerate significant product dilatation without damage.

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