ISPE

KB-0025-Jun12

Fundamental

Knowledge Brief

Packaging Equipment:
Blow/Fill/Seal (B/F/S)
Technology

by Andrew W. Goll Introduction filling, and container sealing. The B/F/S

process is achieved by the five steps
Blow/Fill/Seal (B/F/S) technology is a
specialized aseptic liquid packaging illustrated below.
technology that is rapidly expanding
globally and is considered to be an 1. Thermo
advanced aseptic process by the US plastic resin
FDA and the EMA. Packaging liquid is extruded
pharmaceuticals with B/F/S technology into a tubular
provides the highest sterility assurance shape called
levels available for liquid manufacturing. a parison (the
This Knowledge Brief provides a basic parison is what
introduction to B/F/S technology and ultimately ends
discusses how it may be suited for up being the final container).
pharmaceutical liquid filling applications.
It also provides a basic guidance for 2. When the
what is required to install a system parison
and what complementing utilities, reaches the
cleanrooms, environmental conditions, proper length,
and inspection equipment may be the mold is
considered. closed and the
parison is cut.
The Five Steps of the B/F/S The bottom of
Process the parison is
B/F/S combines the three steps common pinched closed and the top is held in
with conventional aseptic processing place. The mold is then conveyed to
into one completely automated process, a position underneath the class 100
under controlled conditions with no filling zone, where the blowing and
human intervention. These comparable filling nozzles are stationed.
steps are container sterilization, aseptic

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Page 2 ISPE Knowledge Brief
Packaging Equipment: Blow/Fill/Seal (B/F/S) Technology
3. The blowing The five steps of the B/F/S process
and filling occur in 12 to 18 seconds (depending
nozzles are on vial/bottle configuration and filling
lowered into volume) which is the major benefit to
the parison the aseptic process when considering
until it forms B/F/S technology. Quick cycle times and
a seal with complete container aseptic filling/sealing
the neck of without human intervention are the
the mold. reasons B/F/S technology is recognized
The container is formed by blowing by the US FDA and the EMA as an
sterile filtered compressed air into the advanced aseptic technology.1
parison and expanding it against the
walls of the integrally cooled mold Flexibility in Container Design
cavities. After the blowing cycle and One parison can produce one bottle or
vial/bottle formation is complete, the up to 10 vials. The flexibility in container
sterile air is vented from the container design depends on numerous factors
and the sterile liquid product is including product application, vial or
metered into the container through bottle design, and output requirements of
the filling nozzle. After the aseptic the end user.
filling cycle is completed, the filling
nozzles retract to the home position. Products Filled using B/F/S
Technology
Note: in some applications for small The flexibility in container design allows
volume products (0.1 to 10 mL), for a multitude of different products to
blowing air may not be necessary and be filled using B/F/S technology. These
the vial formation will occur by the include ophthalmic products in both unit
use of vacuum which is applied after dose and multi-dose applications. This
the parison is cut. The use of vacuum technology has allowed customers to
enables the molten parison to be develop new preservative free products.
easily contoured into the geometry of This is all due to the quick processing/
the mold cavities prior to the aseptic cycle times, minimal human intervention,
filling process. and excellent product compatibility with
plastics.
4. Separate
sealing molds Respiratory (or inhalation) therapy
close to form products are being filled in varying
the top and container designs, sizes, and
consequently applications. Respiratory therapy drugs
seal the vial/ are typically administered in conjunction
bottle. with humidified oxygen to support
the breathing capacity of individuals
suffering from Chronic Obsessive
Pulmonary Disease (COPD), or more
5. After the simply, diminished or impaired lung
sealing cycle capacity.
is completed,
the mold The most widely used and fastest
opens and the growing market is the Injectable
formed, filled, market. This market fulfills the need
and sealed for injectable products in both Large
vial/bottle is Volume Parenteral (LVP) and Small
conveyed Volume Parenteral (SVP) containers.
out of the machine where further With specifically designed drug delivery
processing such as leak detection, methods, B/F/S offers the ability to
labeling, and packaging may occur. eliminate many of the additional steps
and expenses of conventional aseptic
liquid processing.
Other market segments include Wound
Care, Herbal/Oral Nutraceuticals,
Medical Devices, Beverage, and Isotonic
solution to treat dehydration.
System Success at Achieving
Sterility Assurance Levels of
106 before Autoclaving or Post
Sterilization
The sterile container is formed through
the extrusion process where the
virgin resin is extruded under extreme
temperature and essentially sterilized
through the residence time inside the
extruder as it is being heated and melted
into a semi-molten state.
The aseptic process is achieved through
an automated process which entails
fully integrated Clean in Place (CIP) and
Steam in Place (SIP) processes. The
system offers push button automation of
valve sequencing which will allow for the
start of the initial CIP sequences. The
final results of any CIP sequence must
be proven through customer executed
CIP validation. The sterilization of the
product pathway including product filters
and air filters is achieved via the PLC
controlled automated SIP sequence.
Upon completion of the SIP sequence,
filter integrity testing is also achieved
via the PLC controlled automated filter
integrity test sequence in conjunction
with any number of filter integrity test
instrument suppliers.
After successful CIP/SIP and integrity
test sequences, production is initiated by
means of allowing product flow from the
customer supplied batch/mixing and/or
holding tank to the B/F/S machine. The
product is filter sterilized as it enters the
B/F/S product pathway. After passing
through the sterilizing filters, the product
enters the filling system which is located
inside the Class 100-ISO 5-Grade A,
filling zone. Other options for product
transfer/delivery to the machine are via
bulk sterilization of the product batch.
As regulations differ globally, many
regulatory agencies are working toward
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ISPE Knowledge Brief Page 3
Packaging Equipment: Blow/Fill/Seal (B/F/S) Technology
cohesive regulatory guidance to ensure
patient safety, the proper following of
cGMPs, and drug efficacy. During normal
production the Class 100-ISO 5-Grade
A Environment where aseptic filling
occurs is monitored for both viable and
non-viable particulates. The monitoring
of particles inside the Class 100-ISO
5-Grade A Environment is typically
performed at predetermined sampling
intervals for viable particulate and point
in time or continuous monitoring for
non-viable particulate; this would be
determined by guidelines published for
that region.
Primary Resins Used
The primary resins used for B/F/S
technology are Low Density
Polyethylene (LDPE), High Density
Polyethylene (HDPE), or Polypropylene
(PP). The main differences between the
resin characteristics are driven by market
requirements, product compatibility and
stability, and end user requirements.
B/F/S systems have the flexibility to run
various resins on the same machine. It
is common for an ophthalmic product
filled in LDPE resin running on the same
machine as an injectable being filled in
PP resin. LDPE and HDPE resins can
be terminally sterilized as they require a
lower temperature due to their molecular
structure, whereas, PP can withstand
sterilization temperatures of 121.1°C.
Cleanroom Design
Cleanroom footprints for BFS are small
and economical in design requiring
less use of space adding an additional
cost savings. Cleanrooms should be
classified as class 10,000-ISO 7-Grade
B, static and class 100,000-ISO 8-Grade
C, dynamic with a functioning B/F/S
machine installed inside. This special
classification has been accepted by the
regulatory community for B/F/S due to
the manner in which the mold carriage
travels from the parison head to the
Class 100-ISO 5-Grade A filling zone.
There are two main areas which are
known to generate non-viable particles
during normal production. These are:
1) the carriage transfer process which
takes the cut parison and transfers it
to the Class 100-ISO 5-Grade A filling
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zone, and 2) the parison cutting process
by the hot knife. During the parison
cutting process, a hot knife blade is
electrically heated to a temperature of
1200 to 1400°F. The extreme heat of
the hot knife in contact with the parison
generates non-viable “smoke” particles.
Though not viewed as harmful, the non-
viable particles need to be monitored
and controlled via efficient cleanroom
design to ensure adequate removal of
non-viable particles to ensure that the
area is maintained within established
action and alert limits.
Utility Requirements
The utility requirements to run a fully
functioning B/F/S machine consist of the
following:
• Electrical power
• A chilled water supply, used to supply
the B/F/S machine with cooled/chilled
water, to maintain sufficient flow of
chilled water to the molds, extruder,
and the hydraulic system.
• A dry and oil free compressed air
supply used to run various parts of
the B/F/S machine. The compressed
air is used to actuate various
sequence valves and it also serves
as the source of filter sterilized air
which is supplied to the blowing
and ballooning circuits for vial/bottle
formation.
• Vacuum used in conjunction with the
blowing circuit to ensure proper vial/
bottle formation within the main mold
and seal mold cavities.
• Steam for the sterilization sequence
of the product pathway. Upon
completion of the SIP sequence
steam is no longer required during
normal production.
Leak Detection
Most pharmaceutical applications require
some form of in-line leak detection to
ensure product quality and that the vial
or bottle integrity is not compromised
with the risk of ingress of bacteria into
the liquid solutions. Several methods
of leak detection are in use today; all
have been proven to be acceptable
methods of ensuring product quality and
eventually patient safety.
1. High voltage leak detection is widely
used in the pharmaceutical industry
for all applications from LVP to SVP,
respiratory therapy, and ophthalmic
products.
2. Vacuum leak detection also is widely
used and can easily adapt to the
same product lines.
3. In some applications (where terminal
sterilization is required), a simple
vacuum check after the sterilization
cycle is complete can aid in
determining if leaking vials or bottles
are present. The vial or bottle would
be easily viewed by the distorted or
collapsed shape they take due to
leaking.
4. Another less sophisticated approach
is to perform an Acceptable Quality
Level (AQL) on the entire batch and
perform a dye ingress test. Vials
are submersed into a premixed dye
solution and a vacuum is applied
inside the sealed chamber. A non-
integral vial/bottle will have dye forced
inside, thus making is visible to the
human eye.
Conclusion
B/F/S technology has been available for
50 years, but there have been significant
advances in the last 10 years. This
is primarily driven by improvements
in technology and automation and
the inherent lack of one of the major
contamination sources found in a
cleanroom (people), making this an
inherently robust process.
References
1. FDA Guidance for Industry, Sterile
Drug Products Produced by
Aseptic Processing; Current Good
Manufacturing Practice, Appendix 2
Blow-Fill-Seal Technology, September
2004.
Page 4 ISPE Knowledge Brief
Packaging Equipment: Blow/Fill/Seal (B/F/S) Technology

2. Pharmaceutical Manufacturing and

Packing Sourcer (PMPS) May, 2011.
The article is found in the Aseptic
Filling section page 96, titled “A
Dedicated Environment.”

Acknowledgements
Graphics for this Knowledge Brief have
been provided by Weiler Engineering, Inc.

For Further Information

For more detailed and related
information, the following ISPE
resources are available:

Packaging Community of Practice

(COP):
• Visit the ISPE Packaging COP for the
most current and up-to-the-minute
discussions on B/F/S technology and
other packaging equipment topics.
http://www.ispe.org/communities-of-
practice

About the Author

Andrew Goll is the Technical Sales
Manager for Weiler Engineering, Inc.,
responsible for the Asian market and
technical support to the entire Sales
team. He has more than 18 years
of experience in the Blow/Fill/Seal
community. His broad experiences in
technical roles include research and
development, design engineering,
contract and generic manufacturing,
plant operations, new product
development, and global technical
support to all of Weiler Engineering’s
customers across all continents. He is
a member of both PDA and ISPE. Goll
holds a BS in business administration

•
with a minor in marketing and an MBA
from Webster University.

© Copyright ISPE 2012. All rights reserved.