VALIDATION OF THE CONTAINER CLOSURE
Among the expectations regarding behavior of a container closure, some of them come from pharmacopeias or ICH guidelines while
others are based on glass-vial standards. The list of the relevant tests and expected behaviors are indicated in Table I.
Nevertheless, before starting validation of the container closure, it is crucial to ensure that it is appropriate to use the
vial after gamma-irradiation. Gamma irradiation generates significant ozone. Because the vial is closed, the ozone cannot
exit from the vial, and therefore, its disappearance results mainly from its natural degradation in oxygen. To ensure that
degradation is sufficient to return to acceptable conditions, remaining concentration was calculated on the basis of ozone
half-life (6). As half-life in atmospheric conditions is less than an hour, the ozone level would return back to normal concentration
within 10 hours. In practice, such delay is much shorter than the delivery time from the irradiation site to the filling site,
so there is no concern with ozone content.
Particle presence
Table II: Particles generated by complete process (from vial manufacturing up to product collection) in 2 mL crystal vials.
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According to both the US and the European pharmacopeias, the particle content inside a small volume injection container should
not exceed 6000 for particles > 10 µm and 600 for particles > 25 µm (if the light obscuration particle count method is used).
The method recommends careful withdrawal of the water for injection (WFI) content of several vials (to exceed 25 mL of test
solution) and to pool it into a clean container. Usually, the stopper is carefully withdrawn to perform the WFI collection.
In case of the closed vial, the stopper withdrawal being not feasible, the collection is performed by means of a syringe equipped
with a 23 G needle piercing the stopper (which means that the particles generated during piercing of the stopper for product
collection are included in the results). Particles generated by the movement of the syringe plunger are neutralized by a blank
value of syringe movement.
The results from a typical test, summarized in Table II, show that the particle content is much lower than the acceptable
limits. In addition, these data are roughly two times lower than the particle content in glass vials measured according to
the same procedure. This test is performed routinely to monitor the level of particle presence in vial batches.
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