METHODOLOGY
Table I: Qualitative identification of container, format, source of product contamination, and exposure time.
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The applied methodology can be described by the following four steps. The outcomes of each step are summarized in Table I.
Definition of container types
Several containers are used for aseptic filling of injectable liquid products. The main ones are:
- The ampul, which is the original container and still by far the most frequently used primary packaging throughout the world.
- The open vial, which replaces the ampul in many regions such as Western Europe and North America. Two formats of vial necks
are frequently used, the small neck vials like 2R and 4R and the large neck for 6R vials and bigger. Glass vials are widely
used whereas polymer vial use is still limited.
- The prefilled syringe, which is often used for expensive biological drugs in North America. Again, glass syringes are used
more frequently than polymer syringes. Cartridge technology has been assumed to provide very similar results compared with
prefilled syringes and therefore was not specifically analyzed.
- BFS technology, which is widely used for both small- and large-volume parenteral infusions as well as noninjectable aseptic
applications, such as ophthalmic, respiratory therapy, or nasal drugs.
- Crystal closed vial technology, which has been developed to address, among other things, the issue of contamination risk due
to environment and operators. This vial is made of cyclo-olefin co-polymer (COC) and supplied clean, closed, and sterile.
The vial is filled by a needle piercing the stopper; the trace of the needle is then re-sealed by a laser (2).
Definition of container format
To allow comparison between containers, the focus has been put on containers designed for a product volume of 2 mL, one of
the most frequently used formats for injectables.
Identification of critical surfaces
Critical surfaces for potential contamination are detailed in Table I. The most obvious one is the container itself. The entry
surface provides a good estimate to correlate with risk of contamination rather than the entire internal surface of the container.
Another main surface that may potentially be contaminated is the internal surface of container closure components, such as
the vial stopper and syringe plunger. Before closing the container, these surfaces are fully exposed to the laminar airflow
and are in contact with equipment parts, such as the vibrating bowl and ramps, that may transfer contaminants. Usually, these
container closures are loaded in sorting bowls in large quantities. In such cases, the corresponding exposed surface can be
estimated by the area of the bowl open surface (π × bowl radius2) divided by the number of components inside the bowl and multiplied by the share of surface at risk (i.e., the internal surface
of the closure).
The needle, or mandrel for BFS, is also a source of possible contamination when it is fully exposed to the ISO5 environment.
A contaminant can stick to the needle surface, to a liquid drop, or close to the exit holes and be brought inside the next
vial by the product flow. The needle surface at risk to be considered for the present study is the surface in contact with
either the product or the container.
Quantification of the exposure time
The exposure time is a crucial factor because the longer the exposure time to the ISO5 environment without specific protection,
the higher the probability of contamination.
As an example, the glass vial component is exposed during the cooling process after the depyrogenation tunnel, during the
filling process, and until being stoppered. Any contamination occurring before or inside the depyrogenation tunnel will be
destroyed and therefore be without effect. Any contamination occurring after proper stoppering will affect the external part
of the vial and therefore not the product inside the vial. To ease the use of the model, special events linked to improper
container processing (e.g., equipment stops or break down, or manipulation by operators) have not been taken into account,
but these events would of course lead to higher risk of contamination.
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