To define the shelf-life of vials, irradiated vials were stored for up to five years. On a regular basis, vials were tested
for appearance, container closure, particle content, sterility, and laser reseal ability. Until now, four years of shelf-life
have been validated for the 2-mL vials.
Extractables studies are becoming more and more mandatory. The purpose of the extractables studies is to identify all compounds
that could leach out of both the vial body and the stopper, while leachable studies aim to identify all compounds that actually
leach to the solution. Therefore, the detection of an extractable does not mean that this compound will be present as a leachable
when long-term studies are conducted with pharmaceutical drugs, but it is worth specifically tracking such a chemical compound
when the possibility of it being present exists. To perform appropriate extractable studies, four factors must be taken into
- maximization of contact surface for extraction
- use of aggressive solvents at high temperature
- optimization of extraction time to ensure that all material has been extracted
- use of wide range of detection methods to ensure that no significant material remains undetected.
For each of these key success factors, a method has been set up to ensure optimal extraction.
Based on extractable results, a list of 13 potential compounds categorized as potential leachables was established and these
compounds were followed during compatibility studies.
Beside drug stability studies, the behavior of the vial itself must be assessed because its performance may vary according
to the solution filled inside. Some products can be aggressive to the materials used for the container, leading to significant
leachables, while others can degrade components material. Before final testing with pharmaceutical drugs, preliminary supporting
data can be collected with some of the classical solvents/excipients. The characteristics assessed during long-term compatibility
studies are visual aspect, maintenance of closure integrity, particle generation, and leachables.
The first three tests were conducted in the presence of WFI but additional simulants were selected for leachable studies.
These simulants were WFI, 10% ethanol, phosphate buffered saline, 0.9% NaCl, and 0.5% 2-phenoxyethanol. Vials of 2 mL were
filled with 1.2 mL of simulant and stored 50% right-side-up and 50% upside-down. The last results corresponded to two years
of incubation at 30°C ± 2°C / 35% ± 5% relative humidity and showed that the visual aspect of the vial was not altered, the
closure integrity was maintained, and the particle profile did not change significantly. Regarding the leachables, a one-year
assessment was conducted to notice possible differences. Because no major differences were seen after one year, two of them,
WFI and 10% ethanol were selected for long-term studies (five years). The leachable results showed the presence of two compounds,
acetic acid and formic acid, exceeding 5 ppm. Low leachable quantities of t-butanol and acetone were detected in concentrations
exceeding 0.2 ppm and all other products, including nine of the extractables recommended for follow-up, were either not detectable
or at trace level. It is important to note that these four most abundant compounds in solution belong to the Class III solvent
category according to the ICH Q3C guidelines. In these guidelines, the acceptable daily administration dose for Class III
solvents is fixed at 50 mg, equivalent to more than 40,000 ppm in a vial filled with 1.2 mL. In addition, the full leachable
profile was reviewed by a toxicology expert who did not report any toxicity concern.