The key to Blow/Fill/Seal’s success is that it is a highly automated system
that reduces the main contamination source – people – by minimizing outside interventions.
Plastic containers are not compatible with all products.
The typical resins used in the BFS process are low density
polyethylene (LDPE) and polypropylene (PP). Both materials
have good water vapor barriers but poor gas barrier characteristics. In pharma applications the typical resin has minimized additives giving it a relatively clean extractable profile.
Initial compatibility can be tested in a lab setting by filling
the product into empty sterile BFS containers. The 10 mL
containers are made from a variety of PE and PP materials
and are supplied ready to fill. This cost effective method can
indicate basic compatibility with the plastic resin produced
with the BFS process.
Once basic compatibility is confirmed the next step is
to test the product with BFS technology. A contract manufacturer can provide this service. Within the Contract
Manufacturing Organization (CMO) community there are
capabilities to test a wide pharma and biotech product range
including injectable, inhalation, ophthalmic, vaccine, SVP,
LVP, gels, creams, suspensions, and emulsions. Maropack, in
Zell, Switzerland, opened a BSL- 2 facility for tests, trials and
Blow/Fill/Seal containers are well suited to be considered
when glass containers are not product compatible, such as
product formulations which have active or ancillary components that react with metal ions (e.g. Al 3+, Ca 2+, Fe 2+, Fe
3+, Ba 2+), products which show high pH values (pH > 8.0) [ 5]
[ 6], and when glass breakage during transport is a concern.
The BFS container is fully sealed by a mono-layer polymer
that has consistent expansion and contraction characteristics. This allows the product to be refrigerated or frozen
without damage to the container. With proper container
design the containers can withstand submersion in liquid
Primary packaging can be utilized during phase II clinical
trials. At this point a generic container design can be used. By
phase III the product is in the final packaging type and design.
In both cases it is common for the product to be produced at
a contract manufacturing organization. CMOs have the ability
to make small runs and typically have several stock container
designs available for various applications. BFS users that have
their own BFS filling systems also use CMOs in order to avoid
disruption in their commercial production equipment with the
trial production and other time consuming related requirements.
The BFS container is created inside the machine. This
gives the advantage that there is no upstream container handling: no empty container transport, storage prior to filling,
depalletizing, descrambling, accumulation, washing, or depy-rogenation. A unique container design can be produced and
a positive handoff made to downstream secondary packaging systems. Existing container designs include fills from 50
microliters to more than 1000 mL.
A growing area in pharmaceutical packaging development
is aseptic liquids supplied to medical devices. Here the BFS
container is designed to fit into a device and supply an aseptic
liquid. The BFS container can work as an aseptic cartridge that
is disposable or be permanently intergraded into a single use
device. It is also possible to insert a device into a container.
A test mould is manufactured to produce a container that
can be used to prove out functional operation and then to
produce aseptic containers for stability and clinical trials.
Moving from a completed test container design through
functional testing and onto validation and GMP aseptic filling
is a process that takes between nine and twelve months.
INSPECTION: INTEGRITY AND PARTICLES
FDA guidelines require that all aseptically filled BFS containers be 100% mechanically tested for integrity. The US
Pharmacopeia requires containers for injections to be visually inspected for particles present.
There are several technologies that can be used to test BFS
container integrity. The most prevalent are high voltage leak
detection (HVLD) and vacuum leak detection. Both systems are
reliable and robust. HVLD is a simpler system but it only tests
PHARMACEUTICAL PROCESSING | SEPTEMBER 2014 27 ■
Moving from a completed test
container design through functional
testing and onto validation and GMP
aseptic filling is a process that takes
between nine and twelve months.