RESULTS

Quantification was performed according to the categories in Table I. The information used was obtained from several sources, including equipment users and Internet websites. All the listed operations were assumed to be performed under a unidirectional laminar air flow with a speed of 0.45 m/sec. Turbulences were not taken into account unless specified for some chapters. The quality of viable particle content of the laminar airflow is assumed to meet Class ISO5 requirement and has also been assumed to be identical for all five technologies.

Equipment can have a specific effect as well, because low speed equipment may signify increased exposure time. Therefore, a similar capacity of 150 units/min has been considered.

As listed in Table I, three potential sources of contamination were identified: the open vial, the stopper, and the needle.

For the vial, contamination by airflow can occur through the vial neck. A 2R vial has a neck diameter of 13 mm, with a real opening of 7 mm diameter, according to the ISO standard (3). Only the opening is considered as a source of contamination entry. Contamination on the remaining surface is assumed not to enter the vial after stoppering and therefore does not alter the product quality.

The exposure time, from depyrogenation tunnel until stoppering, is estimated to be approximately 15–20 min based on user comments. A significant part of this time is used to cool down the vial before filling. Contamination occurring when the vial is still hot is not a major risk because bacteria can be killed by intrinsic vial heat. Therefore, the real time at risk was considered to be approximately 8 min.

The second source of possible contamination is the stopper. In the case of filling inside an isolation barrier, the stoppers are loaded either from a sterilization vessel or from rapid transfer port (RTP) beta-bags. In both cases, once the port is opened, the stoppers are exposed to the filling environment. The stoppers are transferred to a vibrating bowl and then brought to the stoppering station through various ramps. A good estimate is that reloading of stoppers takes place every 30–40 min. This means that the average exposure time is a little more than 20 min as reload takes place before complete emptying of the bowl and the ramps.

Regarding the exposed surface, it is necessary to take into account that many stoppers are stacked on each other in a vibrating bowl and therefore not permanently exposed. The vibrating bowl comes in several sizes, but a 600 mm diameter is a good approximation for a line with a capacity of 150 vials/min. The presence of a loading buffer has not been taken into account. The presence in the ramp has been considered negligible compared with the time spent in the bowl and, moreover, stoppers usually present the external part to the airflow, hence a reduced risk. Only the part of the stopper introduced inside the vial presents a risk of contamination, and represents approximately 40% of the entire stopper surface. Therefore, the calculation of exposure is based on the air entering the vibrating bowl and the share of distribution between noncritical and critical stopper surfaces. If a bacterium sticks to the internal surface of the bowl, it is assumed that sooner or later it will transfer to a stopper.

The last component is the filling needle. The filling needle remains exposed during the entire filling process but, considering each vial independently, the exposure time is limited to a single filling time. The critical surface is limited to the area accessible to a drop, and is estimated to be 2 mm² for a standard needle. Another point to consider is that the critical surface is either parallel to the air flow or protected underneath the needle, so the risk of contamination is reduced because there is no perpendicular airflow. Therefore an angle of 30° has been taken into account as flow can be turbulent, especially under the needle holder.

Needle exposure time is limited, because pumps usually have a filling capacity of 2400 small vials per hour according to equipment manufacturers, or one fill every 1.5 s.

Prefilled syringes

The process for syringes is similar to that for vials. Three similar components are involved (i.e., barrel, plunger, and needle) and a parallel evaluation can be conducted. The main difference consists in a reduction of the exposure time for the syringes versus the vials as they are usually not processed through a depyrogenation tunnel but are supplied in ready-to-use tubs.

For the model based on a 2 mL syringe, the selected barrel has an internal diameter of 8.65 mm according to the ISO standard (4). Again, as for the open vial, the barrel opening is considered as a potential source of contamination entry.

With ready-to-use tub packaging, the exposure time for the syringe barrel is limited to the unwrapping process, the exit of syringes from tubs, the weighing time before and after filling for in-process control, the filling time, and the conveying time for all these steps until plunger placement. This time is limited and varies according to equipment complexity, buffer capacities, and speed. A total time of one minute has estimated to start the closing of the first syringe after unwrapping with no buffer assumed. As there are approximately 100 syringes per nest, this represents an average additional time of 20 s for each syringe.

The standard plunger has a front surface of 9.2 mm to ensure tightness in the 8.65 mm barrel. This surface is at risk as it will be directly in contact with the product. The rest of the surface (i.e., sides and back face) represents approximately 85% of the plunger surface. An average exposure time of 20 min, similar to open vial stopper, is a good approximation. The size of the vibrating bowl is smaller compared with that used for open vial stoppers so a diameter of 400 mm has been estimated.

Table II: Quantification of exposure risks based on exposed surface, exposure time and a unidirectional airflow of 0.45 m/s.