Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Formulation
Development
for
Sterile Liquid Products in Blow
FillSeal
Packs
Sterile liquid products are liquid dosage
forms of therapeutic agents that are free
from viable microorganisms (1). Many
sterile liquid products are available
commercially and can be classified
according to their volume, use, and physical
state (see Figure 1) (24). All sterile
products must pass a sterility test. In
addition, any solutions that are injected
directly into the bloodstream (e.g.,
intravenous preparations), poured into body
cavities and surgical areas (e.g., irrigation
solutions), in direct contact with blood (e.g.,
hemofiltration), or introduced into body
cavities (e.g., peritoneal dialysates) must be
formulated as nonpyrogenic preparations
that are essentially free from particulate
matter (3). Hence, parenterals present
numerous challenges that necessitate their
comprehensive
physicochemical
characterization to achieve compatibility of
active drug and excipients. The processing
of sterile liquid products is a highly
specialized area requiring careful evaluation
and stringent control of critical process
parameters to create a robust product that
meets requirements for sterility, pyrogen
level, and
particulate
matter (5).
To varying
degrees,
pharmaceuti
cal
containers Figure 1: Classification of
sterile liquid products.
protect
products from environmental conditions and
minimize constituent loss (6). Although
glass has been the traditional choice for
BFS technology
BFS technology facilitates an advanced
aseptic processing technique that allows
containers to be made, filled immediately,
and sealed aseptically in one continuous
process within the sterile environment of
one machine (7). The process involves the
inflation of a plastic parison with
compressed air to form containers (see
Figure 2). Each cycle takes about 1018 s,
after which a conveying system transfers the
product for further processing. It also is
possible to automatically insert parts such as
a dropper, rubber stopper, or a probe before
sealing the container, thus enabling
innovative packs (8). The introduction of
rubber plugs allows the development of
multidose injections. Such injections would
not be possible otherwise because the plastic
packs cannot be resealed after being
punctured. A high sterility assurance is
provided by a three-stage filtration process:
Table
II:
Corresponding
sterilization time at 106 8C for
different F0 values.
Sorption. Lipophilic actives such as
diazepam and nitroglycerine, oils, and
preservatives adsorb on plastics (20). The
mechanism proposed for such a loss is
partitioning, followed by diffusion (of
lipophilic solute) into the matrix (21). The
correlation of formulation components'
sorption potential and octanolwater
partition coefficients can form the basis of a
formulation strategy to alleviate this
problem (22). Partitioning also is affected by
the pH of preservatives (23). A qualitycontrol approach involves quantifying the
initial level of preservative content,
quantifying the reduced level after the end
of the shelf life, and performing a
preservative efficacy test.
Thermostable
product
filled
in
polypropylene BFS packs withstands the
conventional autoclaving temperature of 121
C, but polyethylene containers cannot
withstand temperatures higher than 110 C
(28). In Europe, sterilization cycles used for
plastic packaging use lower temperatures
and longer cycle times. The BFS process
involves the aseptic filling of a sterile,
filtered formulation, thus resulting in a low
initial bioburden. In such cases, an average
F0 value of 48 is acceptable for terminal
sterilization, instead of the recommended
value of 15 (29). Table II shows the
sterilizing time required to obtain different F
0 values at an autoclaving temperature of 106
C (30). This type of bioburden-based
autoclaving cycle delivers the least heat to
the product and, therefore, can be applied
successfully to polyethylene BFS packs that
cannot
withstand
the
conventional
autoclaving cycle.
transparent
solutions
in
transparent
containers. In this method, product is
exposed to pulses of broad-spectrum, highintensity light (90,000 times the intensity of
sunlight) that kills bacteria without
chemicals, ionizing radiation, or heat. The
combination of aseptic filling of a sterile
product (during the BFS process) and
terminal sterilization using PureBright
technology should achieve an acceptable
SAL and satisfy the regulatory requirements
for terminally sterilized products.
Process development
The integration of processing steps such as
filtration, filling, and sealing offers
advantages over the conventional parenteral
manufacturing process (7). The following
are other advantages offered by BFS
technology:
Scale-up
The BFS process is amenable to large,
uninterrupted batches, even in excess of
500,000
units.
The
process
also
accommodates fill durations of as long as
120 hours. These characteristics increase
productivity and reduce operational costs.
High-temperature exposure during filling.
During the extrusion of polymer melt and
blow-molding, the temperatures reach as
high as 170 C. These high temperatures,
although helpful in destroying microbes,
raise the possibility of the thermal
degradation of a thermolabile product during
the filling process. Unicep's (Sandpoint, ID,
www.unicep.com) "Modified BlowFill
Seal" (MBFS) process was introduced to
address this limitation of the standard BFS
6
Conclusion
Blowfillseal (BFS) technology offers an
attractive alternative to conventional
packages for sterile liquid products.
Automated filling lines under controlled
environmental conditions provide enhanced
sterility assurance. Formulation problems
such as oxidative degradation, loss and
7.
Boehringer-Ingelheim,
"Aseptic
Production
of
Pharmaceuticals
in
Boehringer-Ingelheim Using BlowFill
Seal Technology," Business Briefing:
Pharmatech [CD-ROM]. London: Business
Briefings Ltd., (May 2003), pp. 13.
sterility,
References
8. C.H. Reed, "Recent
Technical
Advancements
in
BlowFillSeal
Technology," Weiler Engineering Company
Web
site,
http://www.weilerengineering.com/images/p
dfs/weiler_tech.pdf, accessed Sept. 5, 2006.
19.
J.B.
Polin,
"BlowFillSeal
Manufacturers Offer Turnkey Solutions,"
Pharmaceutical and Medical Packaging
News,
http://www.devicelink.com/pmpn/archive/04
/09/001.html, accessed April 10, 2006.
21.
"Incompatibility,"
in
The
Pharmaceutical Codex: Principles and
Practice of Pharmaceutics, W. Lund, Ed.
(The Pharmaceutical Press, London, UK,
12th ed., 1994), pp. 311322.
10
11