6 MARCH 2015 ◗ pharmpro.com
ADVANCED ASEPTIC TECHNOLOGIES
maintain filling operations. On the other hand, batch processing of
these components is limited by equipment size and requires additional
operator handling steps, thereby increasing production times and the
risk of contamination. After filling, continuous processing techniques
should be used to transfer partially stoppered vials to lyophilizers,
where they can be loaded automatically with isolated loading systems.
These systems can also unload the lyos and transfer the vials to the
capper for final crimping. Interventions occur through glove ports and
the operators are never exposed to the aseptic environment. Manual
loading and unloading of lyos, however, require many handling steps
by operators who must be in the aseptic environment. These operators
pose a constant risk of contamination and the success of the run often
depends on their aseptic technique. Automation can also be extended
to the cleaning or decontamination of equipment and the aseptic
environments within them. Isolators use vaporized hydrogen peroxide
systems (VHP) for sanitization. These automated systems have cycle
times that can be as quick as two hours and greatly improve the time it
takes to “turn over” a production suite between products.
Single-use disposable systems (SUDS) can also help reduce equipment turnover times. Today’s filling lines can accommodate SUD
product fluid paths and filling needles, allowing these hard to clean
components to simply be discarded. They arrive pre-sterilized in bags
with rapid transfer ports that can easily be docked to the filling isolator.
Implementation of SUDS technology allows manufacturers to focus
less on support functions and more on producing their own products.
The architectural design of large scale facilities can be as important
to production as the process equipment. Creating an optimal layout
and choosing the right finishes can affect how efficiently the facility
operates and how well it holds up to the demands of daily operation
and cleaning regiments. The layout of the facility must directly support
the production steps. As mentioned above, the goal is to keep the filling line running as much as possible. Material flows should be studied
to provide adequate space for staging for both formulation and filling
activities so that the filling line is never waiting for product.
Aseptic facilities are designed to minimize contamination of sterile
products. Choosing the right clean room system can directly affect the
achievement of this goal. Clean room vendors typically offer complete
systems with facility components that are designed to work together.
They also have many pre-engineered details to facilitate equipment
installation and integration. This approach has many advantages over
“Stick built” systems where components are field integrated. Clean
rooms are required to maintain pressure cascades between production
areas and transition zones. Maintaining pressure is critical as these
parameters are validated and monitored. The best clean room systems
offer PVC coated wall and ceiling panels which are chemically welded together ensuring a tight seal. Stick built construction and lesser
clean rooms systems rely on silicon sealant at these joints which can
degrade over time requiring constant maintenance. Other benefits of
clean room systems include quick and clean construction and integral
walkable ceilings which provide maintenance accessibility to interstitial
spaces above the ceiling.
SMALL SCALE/PILOT FACILITIES
Small or pilot scale facilities can be quite different in their design
and the equipment they employ. They tend to produce smaller quan-
tities of higher value products in multiple container types and sizes.
These facilities require innovation and flexibility, but they still need to
adhere to the same regulatory requirements as the larger commercial
facilities. Although the goal of the small facility is still to formulate and
fill product, the batch sizes are much smaller and the facility “turn-
around” time between products tends to be the bottle neck.
Filling line vendors have responded to the need for more flexibility.
Many now offer multi-format machines which can fill a range of containers sizes and types including vials, syringes and cartridges. These
fillers are also available with isolators to improve turn-around times
and reduce risk of contamination as mentioned above. Some suppliers
now even offer smaller, more affordable isolators with plug and play
baseplates allowing filling systems to be switched out depending on
the process needs and production steps. These isolators are modular
and can be combined in arrays to support a variety of production
methods. Other suppliers offer flexibility by integrating handling of
both syringes and vials in the same machine, sometimes utilizing
robotics. Isolated filling lines can also take advantage of rapid VHP
chambers which can be used to sanitize and transfer components into
the isolator at any time. Recent developments have led to validated
sanitization cycles as quick as twenty minutes.
In addition to isolator technology, SUDS can greatly improve the
efficiency of a small volume facility. Disposable systems eliminate the
need for vessel cleaning and lend themselves to the smaller formulation batch sizes of pilot facilities. Of course, the small scale filling equipment can also take advance of the disposable fluid paths and filling
needles to speed up turnover times. Disposable aseptic connectors
provide additional flexibility as they are easy to use and don’t require
the cleaning and sterilization of traditional aseptic connections.
The architectural design of small volume facilities can also play a
key role in their functionality. When isolators are utilized the facility can
take advantage of the “ballroom” approach where the filler is central
in the layout within a large open room and all other support functions
surround it. This provides the required filling flexibility along with
adequate separation of critical production steps. Conventional aseptic
facility designs require separation of aseptic operations from non-criti-cal production steps. Such facilities are less efficient because of the procedures and steps required for entering an aseptic environment. They
tend to be less flexible and harder to adapt to changing processes.
Pre-engineered clean room systems can also be utilized in these
smaller facilities as the benefits mentioned above still apply. A risk
assessment can be done to determine which approach is best depending on the facility location, available skilled labor, project schedule and
Designing aseptic facilities to meet today’s product demands
and regulatory requirements can be quite a challenge. Fortunately,
advancements in technology and knowledge of operational requirements continue to lead to the development o f equipment and components which respond to these needs. The technology alone, however, cannot guarantee an efficient and productive facility. It is important
to first understand the business and operational goals of the facility.
Only then can a fully integrated facility be developed which meets
these goals and fulfills the business objectives.