Post-washing and post-siliconization
After the stoppers have been washed, a number of quality control checks should be performed.
Mechanical and material tests
- Compression test. A compression test is performed to determine the behavior of materials subjected to compressive loads. Loading
is usually done at a uniform rate (in/min).
- Penetrability (i.e., what happens when a needle passes through the stopper): Assessments can be made of the insertion force,
break loose force, and extrusion force. One common issue that can arise is the generation of rubber particles cut from the
closures when needles are inserted, a phenomenon sometimes referred to as coring (5).
- Assessment of dimensions and flexibility.
Many material tests are conducted by testing a selection of closures using a high-speed color sensor that examines the top,
bottom- side surface, and inside of the closure.
- Resistance to sterilization. This requires consideration of two questions: how does the rubber of the stopper react to different
types of sterilization, such as gamma irradiation, ethylene oxide, and steam sterilization, and does the stopper become more
brittle over time?
- Particle testing.
- Tests for extractables and leachables: Extractables are chemical substances that are obtained by exposing the packaging to
a variety of solvents under exaggerated incubation conditions of time and temperature (6). Leachables differ from extractables
in that they are chemical substances that migrate under normal conditions of use from the stopper into a drug product. Leachables
are, therefore, a subset of extractables; all extractables are potential leachables of toxicological concern (7).
- Silicone oil determination: The effect of subvisible silicone particles should be assessed, because these can cause aggregation
with proteins, and the new complex can potentially trigger an immunochemical reaction within the body of the patient receiving
- Cytological testing.
- Bioburden assessment (such as <5 CFU/stopper). Some manufacturers undertake an examination for mesophilic counts while others
focus on examining for thermophilic bacteria, because such microorganisms will be the most resistant to the sterilization
- Bacterial endotoxin testing (such as <1 EU/stopper). The testing of closures for endotoxin, using the Limulus amebocyte lysate (LAL) method, is quite difficult in terms of method validation because the endotoxin challenge to the rubber surface
can prove to be tricky to recover.