Pharmaceutical Manufacturing Handbook: Production and

PROCESS SELECTION AND DESIGN 103
diffi culty involved in opening ampoules while at the same time avoiding problems
with glass particulate or microbial contamination has reduced their popularity. The
use of plastic containers (as vials, ampoules, or syringes) is increasingly common
given their reduced weight and resistance to breakage. Blow - fi ll seal (BFS) and
form - fi ll seal (FFS) are utilized for the fi lling of numerous ophthalmic and other
noninjectable formulations in predominantly low - density polyethylene (LDPE)
containers. With the exception of ampoules and BFS/FFS, an elastomeric closure
system is also necessary to seal the containers. Some delivery systems (i.e., prefi lled
syringes, multichamber vials, and others may require more than one elastomeric
component to operate properly. In the case of vials, an aluminum crimp is applied
to secure the closure to the vial. Prefi lled syringes may require the preparation and
assembly of additional components such as needles, needle guards, stoppers, diaphragms,
or plungers, depending on the specifi cs of the design. Lyophilization is
required to ensure the stability of some formulations and requires the use of closures
that allow venting of the container during the freeze - drying process. Full
seating of the closure is accomplished within the lyophilizer using moving shelves
to seat the closure.
Glass is ordinarily washed prior to sterilization/depyrogenation to reduce contamination
with foreign material prior to fi lling. In aseptic fi ll processes, the glass is
then depyrogenated using dry heat. This can be accomplished using either a continuous
tunnel (common for larger volumes and high - speed lines) or a dry heat oven
(predominantly for small batches). The depyrogenation process serves to sterilize
the glass at the same time, and thus the glass components must be protected postprocessing.
This is generally accomplished by short - term storage in an ISO 5 environment
often accompanied by covering within a lidded tray. There are suppliers
that offer depyrogenated glass vials and partially assembled syringes in sealed packages
for fi lling at a customer ’ s site. In this instance, the supplier assumes responsibility
for the preparation, depyrogenation, and aseptic packaging. Glass ampoules are
available presealed and depyrogenated; the end user has merely to open, fi ll, and
reseal the syringe under appropriate conditions.
Plastic components (whether container or closure) can be sterilized using steam,
ethylene oxide, hydrogen peroxide, or ionizing radiation. The γ irradiation is accomplished
off - site by a subcontractor with appropriate expertise as these methods are
considered the province of specialists because of the extreme health hazards directly
related to the sterilization method. Electron beam sterilization may also be done
by a contractor, although compact lower energy electron beam systems have been
introduced that allow sterilization in - house. Steam sterilization is ordinarily performed
in house, though many common components are becoming available presterilized
by the supplier. Preparation steps prior to sterilization vary with the
component and the methods used to produce the component. Rubber components
are washed to reduce particles, while this is less common with plastic materials.
Syringes vary substantially in design details and can be aseptically assembled
from individual components. However, increasingly, these are supplied as presterilized
partial assemblies in sealed containers.
The BFS and FFS are unique systems in that the fi nal container is formed as a
sterile container just prior to the aseptic fi lling step. The BFS requires careful control
over the endotoxin content of the LDPE (and other polymeric materials) beads
used to create the containers as well as the melting conditions utilized to form them.