Potential effect of exposure
Aseptic filling is, as its name indicates, a process in which sterility is not guaranteed. Despite recent developments such
as isolation technology, the risk can never be completely eliminated. Several sources of potential contamination can be identified
in aseptic filling including the quality of air supply delivered to the filling line, operator presence, partial sanitization,
contamination during transfer, and operator errors.
International GMP standards require aseptic filling to be performed in a Class ISO5 environment according to ISO 14644-1 where
acceptable particle content is defined (7). European standards further refine the definition as they introduce the concept
of viable particles (i.e., colony forming units or cfu). The Revision of Annex 1 of the Eudralex (8) has defined that the
content per cubic meter of air should be less than one cfu. The concept of using settle plates is also present, with a limit
of less than one cfu settled by 4 h on a 90 mm plate.
Very few monitoring data are publicly available but Vetter has communicated results obtained at the International Society
of Pharmaceutical Engineering (ISPE) meeting in Tampa in 2006 (9). These results cover four years of activity from 2002 to
2005 on four syringe filling lines operated under a restricted access barrier system (RABS) in a Grade B clean room with the
additional constraint that doors cannot be open during operations. During this period, they performed approximately 14,000
environment controls (e.g., air sampling, settle plates, and contact plates) and recorded 11 deviations, approximately 0.1%
of all the environmental monitoring measurements.
Figure 1: Number of contaminated vials per million vials filled assuming the presence of one colony forming unit per 5,000
m3 of air. BFS is blow-fill-seal. (FIGURE COURTESY OF THE AUTHOR)
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Assuming such a deviation rate is representative of aseptic filling under a high quality barrier system, it can be realistically
evaluated that there is one cfu every 5,000 m3 of air. As a result, the risk of contamination in each type of container is illustrated in Figure 1.
Figure 1 shows that the risk of contamination for prefilled syringes is about one container per million. This value is in
agreement with the media fill data communicated by Vetter during the same ISPE conference in Tampa (9). They reported to have
filled, on the four equipment lines protected by RABS, one million media fill units with one case of contamination.
Reduction of exposure risk affects barrier requirements
As two technologies provide clearly different exposure risk compared with the others, barrier constraints to surround filling
equipment for these containers have been challenged by the industry. BFS, being widely used for many years, has received particular
attention from the authorities, and it is well accepted that the filling equipment can be surrounded by a Grade C clean room
according to Annex 1 from the Eudralex (8). On the contrary, a Grade C environment for open vials and syringes imposes the
use of isolators whereas RABS must be located in ISO7/Grade B environment according to the same source. The only restriction
for BFS is that operator gowning should meet the requirements of a Grade B environment (8).
No definition has been set for closed vial technology, because it has been on the market only a short time. Nevertheless,
the manufacturing of the first product submitted for approval has been based on the philosophy that the container provides
additional protection compared with open containers.
Therefore, a new barrier has been defined, built, validated in ISO8 environment, and presented to the authorities. This barrier,
called closed vial filling system (CVFS) containment, is defined as:
"An aseptic filling system providing an environment achieving uncompromised Class 100 / Grade A / ISO 5 protection that surrounds
containers which are delivered closed and sterile inside, are filled through their stoppers and then immediately re-sealed
to preclude the possibility of microbial ingress."
The CVFS is suitable for installation in an ISO8 or Grade C clean room as long as the following key characteristics, defined
by a quality-by-design process, are respected:
- Only closed containers are processed inside the containment.
- The containment is made of a rigid wall enclosure that provides full physical separation of the aseptic processing operations
from operators.
- HEPA-filtered unidirectional air flow is continuously supplied from the ceiling of the enclosure. The environmental control
system operates primarily on the principle of aerodynamic separation (air overspill) as defined in ISO 14644-7. An open bottom
with air exit inside the surrounding environment is appropriate for classical products. For highly potent or toxic products,
a closed bottom is recommended to maintain operator protection. In the case of an open bottom, design prevents any accidental
access of operator or turbulence to the critical area.
- Doors must stay permanently closed until the batch is completed and the line has been cleared of all finished goods. Doors
are locked and interlocked with records of opening by alarms during operation. In the case of a door opening, all material
still present inside the CVFS (e.g., empty vials, filled vials, bulk in fluid path, caps) must be considered as contaminated
and must be discarded.
- Doors must be fully equipped with gaskets to prevent intrusion of contaminants.
- Glove ports are used to access all areas of the enclosure that must be reached by an operator during filling operations.
- Entry of materials, such as closed and sterile containers, sterile caps, sterile fluid paths, environmental monitoring materials,
and tools, is performed via transfer systems that prevent exposure of sterile surfaces to operators and environments which
are not Class 100/Grade A/ISO 5. Among potential solutions are:
o Entry through rapid transfer ports (RTP) using beta-bags for solid parts or SART connector for liquids
o Entry through vapor hydrogen peroxide (VHP) airlock
o Entry through an e-beam sterilization tunnel to ensure sterility of critical surfaces (e.g., stopper top surface).
The recommended cleaning procedure of a CVFS is a high-level disinfection of all non-product contact surfaces with an appropriate
sporicidal agent before batch manufacturing. Performance of sanitization by VHP can also be foreseen but in the case of an
open bottom, the VHP would address the entire filling room.
All product contact parts (i.e., needle, tubing) must be sterilized by either irradiation or autoclave. Entry of these parts
must be conducted according to the above techniques for material entry to maintain an uncompromised sterility assurance level.
Media fill data using closed vial filling system
Table III: Compilation of media fill data using closed vial technology. CVFS is closed vial filling system.
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Closed vial technology has been recently developed and equipment availablity is limited, so media fill data sets are not as
large as those from other technologies. Therefore, media fill data have been compiled from various sources as shown in Table
III.
In addition to the data collected in pharmaceutical environments, challenging media-fill studies have been conducted, one
in a workshop with the operator gowned as for ISO8 environment and one in an ISO8 clean room with the operators gowned as
for ISO8 requirement but without a glove installed on the CVFS. The outcome of the first series of tests, with five media
fill runs generating 26313 media fill units, is that no contaminated unit has been seen. The second test, performed on a much
smaller quantity (523 vials) also found that no vials were contaminated despite the operator entering his arms with simple
glove protection only inside the barrier to set up filling tubing and for other interventions..
Similar challenge studies have previously been conducted and the results published for BFS technology (10, 11).
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