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E-BOOK
BLOW/FILL/SEAL:
AN ADVANCED ASEPTIC
PACKAGING TECHNOLOGY
SPONSORED BY
BLOW-FILL-SEAL: AN ADVANCED
ASEPTIC PACKAGING TECHNOLOGY
SPONSORED BY
TABLE OF CONTENTS
03
Machine Operation
04
Historical/Current Regulatory Viewpoint
05
Process Advantages
06
What kind of containers may be produced?
07
B/F/S Inspiration Image Gallery
11
Drivers Affecting Innovation and the Use of B/F/S for

Legacy and New Drugs.
12
Resin Choices/Examples of Container Cost Savings
13
Topics of Concern
15
Company Profile
2
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Machine Operation
The B/F/S process enables a container to be formed, filled, and sealed in one
continuous, integrated operation using a single automated machine.
Blow/Fill/Seal (B/F/S) aseptic processing in parenteral manufacturing
enables the automated formation of a plastic container, aseptic filling
of the container with a liquid, and the hermetic sealing of the container,
all in a few seconds using one machine. Because packaging of the
formulated drug takes place under aseptic conditions without any
human intervention, it provides increased product safety.
The automated nature of the process leads to:
lower energy consumption
reduced waste generation
lower carbon footprint
In addition, the resins used to form the plastic containers are recyclable, and plastic
containers do not shatter like glass. Furthermore, with most advanced B/F/S systems,
numerous different container shapes can be produced, and today pre-molded, pre-sterilized
inserts can be added once the container is filled, allowing for more delivery options.
Limit Human Intervention and Effectively Reduce Airborne Microbial

bioburden and particulate levels and enhance
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stertility assurance and patient safety.
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Historical
Blow/Fill/Seal (B/F/S) was originally developed in Germany
and has been present in the U.S. since 1968
Technology Evolution
Initial thrust in the U.S. was centered around food and dairy products
(juices, fruit drinks, milk).
Non-sterile medical devices (douche and enema)
Sterile devices, diagnostics and pharmaceuticals
(respiratory diluents, RT drugs, ophthalmics)
In 1993 the first biologic was approved for packaging with B/F/S technology
General trend towards the manufacturing of injectable drugs
Current Regulatory Viewpoint
Provide Critical
Advantages for
Sustainable Initiatives
for Processing and
Packaging
Pharma Liquids.
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Considered an advanced aseptic technology when operated properly

Can be superior to conventional filling technologies under a unique set of standards

- 2004 FDA Guidance for Industry Sterile Drug Products
Produced by Aseptic Processing Appendix 2
Current technological advances are superior to legacy systems
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The Process
Thermoplastic resin
is extruded into a tubular
shape called a parison.
When the parison

reaches the proper
length, the mold indexes,
pinching the bottom of the
parison closed. The top of
the parison is held open
while the parison is cut.
Process Advantages
Why Do Companies Typically
Use B/F/S Systems?
Flexibility in Packaging Design
Low Operating Cost
High Degree of Sterility Assurance
Small Space Requirement
Limited Component Inventory
Limited Number of Operators Required
The mold is
conveyed into position
under the blowing/filling
nozzle assembly. The
nozzle is lowered into the
parison, forming a seal
with the neck of the mold.
The container is formed
by vacuum or assisted
by blowing with sterile
filtered air, expanding the
parison against walls of
the integrally cooled mold
cavity. While in position,
the sterile air is vented
from and sterile liquid
product is metered into
the container through the
fill nozzle.
The fill assembly

retracts and separate
sealing molds close to
form the top, hemetically
sealing the container.
The mold opens and

formed, filled and sealed
container is conveyed out
of the machine.
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What kind of containers may be produced?

Vials with inserted tip / cap
Vials with a twist-off and re-closeable
Multi-dose use bottles
Eye wash and contact lens solution
Unit Dose Injectable
Respiratory care
Electrolyte and Sport Drinks
Rubber stopper insertion
Euro Cap
Spike Top
B/F/S INSPIRATION
IMAGE GALLERY
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PAGES TO SEE 16 DIFFERENT
USAGE EXAMPLES
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B/F/S Inspiration Image Gallery 1/4
Injectable-SVPs 2-5ml small volume parenterals
Injectable-SVPs 10-100ml small vol. parenterals
Injectable-Large volume parenterals
Injectable-SVP using insertion technology
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Injectable-LVP design options
Eye Care-Spike top containers in 5-20ml
Eye Care-Tip/cap multi dose vialsCare-Tip/cap

multi dose vials 5-20ml
Eye Care-eyewash, contact lens solution bottles
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Eye Care-Unit dose for one time ophthalmic use
Biologicals vial pack
Respiratory Therapy-nebulizer and PP bottle, 500 ml
Respiratory Therapy-R/T unit dose 0.5 - 3ml

vials in LDPE
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Herbal/Oral Nutraceuticals
Douche, Enema
Irrigation/wound cleaner bottles
Beverage electrolyte, sport drinks-High Res
10
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Drivers Affecting Innovation and the

Use of B/F/S for Legacy and New Drugs.
Which one of the following considerations would most likely lead you to
develop your NEW, INNOVATIVE DRUG PRODUCT in B/F/S technology?
1. Current production issues with particulates in glass containers 31.6%
2. Flexibility with container design (geometry, unit dose format, etc.) 31.6%
3. Desire for more user friendly drug delivery system 23.7%
4. Improved stability of the product in plastic 13.2%
A comparison of
traditional packaging
v. Blow/Fill/Seal
technology
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Which one of the following considerations would most likely lead you
to develop your LEGACY DRUG PRODUCT into B/F/S technology?
1. Current production issues with particulates in glass containers 40%
2. Desire for more user friendly drug delivery system 31.4%
3. Improved stability of the product in plastic 17.1%
4. Flexibility with container design (geometry, unit dose format, etc.) 11.4%
Source: PDA Europe Conference on Parenteral Packaging, March 2015.
11
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Resin Choices for B/F/S Processing

Depends on stability of products
Multi-dose use bottles

- LDPE, HDPE, P.P.

- Low, Medium and High Density Polyethylene. Barrier properties improve
as density increases, clarity of container improves as density decreases

- Polypropylenes. Excellent barrier properties and good clarity
and high temperature terminal sterilization
Examples of Container Cost Savings
Maximize Uptime,
Minimize Changeover
time and increase
overall equipment
effectiveness (OEE)
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3ml Vial
Cost of Conventional Vial with Closure only ...................... $0.07
Cost of B/F/S vial incl. all operating costs ..................... ($0.036)
Savings Per Bottle ........................................................... $0.034
Savings Per Year .......................................................... $1.85MM
Assumptions:
B/F/S costs include labor, utilities, resin, maintenance and straight line depreciation
over 120 months. Costs are dependant on geographic locations.
Conventional Vial costs are for glass vial and stopper only!
This calculation does not include any operating costs.
12
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Topics of concern
Visual inspection - Traditional visual inspection methodology (either automated or human based) should be
evaluated due to opacity of a particular resin used to produce the container, as well as the product characteristics.
The current gold standard as defined by USP (human inspection) is normally used for B/F/S processes.
Alert and action limits for non-viable particle counts The B/F/S process presents an inherent low risk for
non-viable particle generation. These limits are typically user-defined parameters, based on regulatory guidance
and appropriate risk analysis for specific products.
Container Closure Integrity and Fill Volume Verification - Camera systems can be employed to observe liquid
levels and general vial/bottle integrity at the exit from the B/F/S machine. These systems need to be evaluated
on a case by case basis for feasibility based on container geometry and resin selection.
Labeling Options Vials/bottles produced in the B/F/S process can be embossed by engraving the mold (e.g. Lot
and Expiration as well as product information). This process provides an extra level of security (anti-counterfeiting
measure). Labels can be affixed to the top or bottom tab or directly to the body of a B/F/S container (following
regulatory standards). Laser etching or direct printing can be used in lieu of a label, if appropriately qualified.
Parametric Release Certain resins and post-B/F/S sterilization processes (e.g. autoclave) can be utilized to
provide potential for parametric release of products.
Resin Qualification Selection, use and handling of resin is a key component of the B/F/S process. Resin
should be stored/dispensed from a controlled, non-classified area (as a minimum). Temperature and humidity
controls are recommended. Extractable/leachable profiles should be performed as part of the qualification
process. Use of regrind resin in vial/bottle processing should not exceed 50% and should
be strictly monitored per regulatory standards.
13
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Topics of concern CONTINUED

Interventions The B/F/S process is a fully automated process, designed to produce a formed, filled and
hermetically sealed product without human intervention. During the normal operation of a B/F/S machine,
certain processes may require appropriately gowned personnel (per regulatory standards) to enter the clean
room. All interventions should be documented with appropriate SOPs and should be part of the B/F/S
qualification process (ie media fills).
Viable particulate sampling procedures Specific user-defined sampling procedures should follow
normal cGMP guidance. Typically, sample points are established in critical locations within the B/F/S machine
environment. Viable particulate contamination is extremely rare due to the inherent safety of the B/F/S process.
Blow/Fill/Seal Insertion Technology Increases

Flexibility for Drug Delivery
Advanced B/F/S machine designs allow the capability to incorporate the
addition of pre-molded, pre-sterilized components (inserts) into the basic container.
These inserts, including items such as rubber and silicone stoppers, and tip-and-cap dropper
units for eye drop containers (used to deliver a calibrated drop), are attached to the container
after the blowing and filling process, prior to final sealing step. The application of inserts has
allowed B/F/S technology to advance and expand into product markets which were previously
unavailable, such as intravenous drug administration,
solution irrigation and ophthalmic dropper units.
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14
Weiler Engineering, Inc.
About the Author
1395 Gateway Drive, Elgin, IL 60124

PHONE: 847/697-4900 - FAX: 847/697-4915
Website: www.asep-tech.com
Chuck Reed has

extensive experience
in specialized
equipment design
and manufacture,
process technology
and pilot plant design
and construction.
Weiler Engineering, Inc. is a world leader in providing

sterile, aseptic liquid packaging equipment for
pharmaceutical and healthcare applications. Weiler is
committed to the highest standards of excellence and
to further expanding products and systems to enhance
patient care.
Weilers proprietary ASEP-TECH Blow/Fill/Seal packaging
machines produce shatterproof, durable, sterile aseptically
packaged products in one uninterrupted operation on a
single, compact machine frame without human intervention,
ensuring that parenterals, injectables, ophthalmic solutions,
and respiratory drugs reach the marketplace in the most
sterile, cost-effective manner possibleevery time.
The ASEP-TECH System from Weiler is the culmination
of more than 50 years of innovation in machine design
and sterile process development, resulting in the most
advanced aseptic liquid packaging process available
today through the application of Blow/Fill/Seal
technology. Our Vision - Building quality equipment
profitably, Fostering innovation and Satisfying customers.
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He is a 15+ year member of both PDA and ISPE, is

past Chairman of the ISPE Packaging Community
of Practice and continues to serve on this COP
steering committee. He is an author for the ISPE
Packaging, Labeling and Warehousing (PACLAW)
Baseline Guide. He is currently Chairman of the
PDA Blow/Fill/Seal Interest Group, member of the
PDA Blow/Fill/Seal Technical Report Task Force
and a chapter author in the PDA 2-volume Aseptic
Processing text. Mr. Reed holds a Bachelor of
Science in Chemical Engineering from Clarkson
University and a Master of Science in Management
from National Louis University.
Email solutions@weilerengineering.com
to contact Chuck.
15
ASEPTIC PACKAGING TECHNOLOGY APPENDIX
SPONSORED BY
BLOW/FILL/SEAL:
AN ADVANCED ASEPTIC
PACKAGING TECHNOLOGY
APPENDIX
16
Advances in Aseptic Blow/Fill/Seal

Processing of Pharmaceutical Liquids Improve
Product Integrity and Patient Safety
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The latest improvements in aseptic Blow/Fill/Seal technology are providing

more streamlined automation of critical B/F/S processing areas, while limiting human
intervention and effectively reducing airborne microbial bioburden and particulate
by Chuck Reed, B.Sc/MS, Director, Sales & Marketing, Weiler Engineering, Inc.
Aseptic Blow/Fill/Seal (B/F/S) systems for the processing of pharmaceutical liquids have experienced rapid
and growing acceptance by the pharmaceutical industry over the past 20 years. This has been accelerated
by enhancements made to aseptic B/F/S processes
based on pharmaceutical industry input and to accommodate the requirements of regulatory agencies.
These enhancements were designed to improve product integrity and help ensure patient safety. As a result,
the United States Food and Drug Administration and
the United States Pharmacopoeia now characterize
modern B/F/S technology as an advanced aseptic
process, indicating its use as a preferred technology
over other aseptic systems and a better solution for the
sterile, aseptic processing of pharmaceutical liquids.
Aseptic B/F/S systems offer a unique combination of
flexibility in packaging design, low operating cost and

a high degree of sterility assurance. Due to its design
and functionality, B/F/S processing inherently produces
very low levels of particulate matter, and much of the
potential for microbial contamination in its critical areas
is mitigated by the absence of human intervention in
these areas.
Microbial contamination is a serious issue for companies manufacturing liquid pharmaceutical formulations.
Such liquids are ideal growth areas for bacteria like Salmonella, Escherichia coli and Staphylococcus microbes
that have been found in various liquid drug products.
A supposedly sterile, but contaminated product may result
in deterioration of the drug
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CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of

Pharmaceutical Liquids Improve Product Integrity and Patient Safety
and loss of potency, and with parenterals can cause pyrogenic reactions after administration to patients. The
majority of liquid drug product contamination over the
past several decades has come about from products
produced in conventional (non-B/F/S) aseptic processing facilities. In conventional aseptic processing, the
drug product, container and closure are subjected to
sterilization processes separately, and then brought
together. There is no further processing to sterilize the
product after it is in its final container, therefore it is
critical that containers be filled and sealed in an extremely high-quality environment.
Automation Upgrades Improve Sterility
Assurance in the B/F/S Critical Zone
Aseptic B/F/S technology integrates blow molding, sterile
filling and hermetic sealing in one continuous operation to
produce aseptically manufactured pharmaceutical liquid
products. Unique to aseptic B/F/S systems compared to
traditional aseptic processing, is its capability for rapid container closure and minimized aseptic interventions.
The most advanced aseptic B/F/S systems are quite automated, designed to require minimum human access and
reduce risk to the products integrity, while operating in a
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classified environment. Various in-process control parameters, such as container weight, fill weight, wall thickness
and visual defects provide information that is monitored
and facilitates ongoing process control. Its containers are
formed from a thermoplastic granulate, filled with a liquid
pharmaceutical product and then sealed in a continuous,
integrated and totally automated sequence the critical
fill-zone area is shrouded under a continuous flow of positive-pressure sterile filtered air. The B/F/S cycle is completed within seconds. This reduces the amount of components
contacting the product, and limits operator intervention
particularly with system changeovers and cleaning.
Recent B/F/S equipment designs employ the use of specialized measures to reduce particle levels and minimize
potential microbial contamination of the exposed product
in the plastic extrusion and cutting zone. Non-viable particles generated during the plastic extrusion, cutting, and
sealing processes are thoroughly controlled.
Provisions for carefully controlled airflow protect the product by forcing created particles outward while preventing
any inflow from the adjacent environment. This B/F/S zone
of protection is continually supplied with HEPA-filtered air,
by an air shower device (shroud).
Air in the critical filling zone
18

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meets Class 100 (ISO 5) microbiological standards during

operations. Sterile air management within this critical zone
is typically verified through environmental monitoring for
the presence of non-viable particulates.
more than 99 percent. The KleenKut mechanism assures that

non-viable particles 0.3m to 10m in size are significantly
reduced in quantity compared with the volume of particles
produced during the use of a hot-knife cut-off mechanism.
Non-viable particles in the B/F/S process primarily originate from the electrically heated cut-off knife contacting
the molten parison (an extruded tube of hot plastic resin
through which sterile support air passes during the extrusion sequence). Past attempts to manage non-viable particulate generation in this zone of protection were targeted to
the removal of particles after they were produced. Included
in recent improvements was the development of parison
shrouding, which produces a controlled air environment by
employing an exhaust blower system with differential pressure controls in conjunction with containment ductwork in
the parison cut-off area, to siphon away smoke created by
the hot knife a heated high-resistance wire.
The FDAs 2004 Guidance for Industry Sterile Drug Products

Produced by Aseptic Processing states that the design of
equipment used in aseptic processing should limit the
number and complexity of aseptic interventions by personnel. Both personnel and material flow should be optimized
to prevent unnecessary activities that could increase the
potential for introducing contaminants to exposed product,
container-closures or the surrounding environment. It states
further, that airborne contamination is directly related to the
number of people working in a cleanroom and the level of
congregation by personnel in areas where critical aseptic manipulations are performed.
A new technology was introduced to eliminate the generation of the parison-cutting smoke altogether the KleenKut parison cut-off mechanism. The device is an automated cold-knife that accomplishes the cutting of the parison
without the use of a heated high-resistance wire. It eliminates
smoke generation through the application of ultrasonics,
effectively reducing particulate generation at the source by
Any intervention or stoppage during an aseptic process can

increase the risk of contamination. The design of equipment
used in aseptic processing should limit the number and complexity of aseptic interventions by personnel.
19

Reduced Airborne Microbial Bioburden in Recent
Challenge Study of Advanced B/F/S System
Challenge studies on aseptic B/F/S systems have been
performed over the past 20 years which have correlated the
microbial bioburden of environmental air in a B/F/S fill-room
to the potential contamination rate of product which is filled
on machines in those rooms. These studies have led to an
increased understanding of the capabilities of aseptic B/F/S
technology in the production of sterile products.
B/F/S system manufacturers should base their product development on such studies, including materials testing specifically for microbial challenges, which have been supported with scientific evidence that the researched machines
function within the standards of accredited agencies.
One of the more recent B/F/S challenge studies was conducted in 2004 by Cardinal Health, Inc. and Air Dispersions,
Ltd. entitled Evaluation of Blow/Fill/Seal Extrusion through
processing of Polymer Contaminated with Bacterial Spores
and Endotoxin, a study that was carried out to further the
understanding of the extrusion process and its impact upon
the quality of Blow/Fill/Seal product. Controlled challenges were conducted to the extrusion system, comprising
low-density polyethylene granulate contaminated with Bacillus atrophaeus endospores and Escherichia coli bacterial
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endotoxin. The challenge was performed with an advanced

aseptic B/F/S system supplied by Weiler Engineering, Inc.
Sterility of B/F/S polymeric containers, materials and processes is validated by verifying that time and temperature
conditions of the extrusion, filling and sealing processes are
effective against endotoxins and spores. This report states
The extruder challenge studies, employing spore polymer
and endotoxin polymer, have provided definite evidence
for polymer extrusion having the capability to produce vials
free of viable microorganisms and possessing acceptable
endotoxin levels.
The challenge study demonstrates a uniform capability of
achieving high sterility assurance levels (10-6 SAL) throughout the entire process. Even higher sterility assurance levels, approaching 10-8 SAL, have been achieved using high
levels of airborne microbiological challenge particles.
A critical aspect of B/F/S technology is its pyrogen-free
molding of containers and ampoules. Extensive experiments in this challenge study confirm the efficacy of the
B/F/S extrusion process, having been performed using
high levels of spores and endotoxin-contaminated polymer
granules. Results demonstrated
fractional spore contamination
20

levels of less than 1x10-6, and a three-log reduction in
endotoxins with the probability of a non-sterile unit (PNSU)
approaching one in one million.
Expanded Options for B/F/S Packaging and
Delivery Solutions of Pharmaceutical Liquids
B/F/S processing resins, polyethylene and polypropylene,
used to produce aseptic containers for injectables, ophthalmics, biologicals and vaccines are generally considered inert by the FDA, and many of the blow molding resins used
in B/F/S processing have received international acceptance
as suitable for pharmaceutical liquids applications. These
inert materials do not contain additives, have low water vapor permeability, and are easy and safe to handle in critical
care environments such as hospitals.
Of particular interest within the pharmaceutical industry, is
the use of plastic material for the B/F/S production of small
volume parenterals. Plastic ampoules offer significant advantages over rubber-stopper glass vials. There is the safety
issue glass vials are subject to breakage, both in transit
and while being administered. Handling glass containers
always involves a certain amount of risk of lacerations and
glass splinters. Glass ampoules generate a fine array of
small glass particles during opening. Glass is typically transported in cardboard boxes that can contain mold spores,
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such as Penicillin sp. and Aspergillus sp., as well as bacteria

like Bacillus sp. Paper, also used in the shipping of glass,
can also contain mold spores. The rubber closures used on
the glass containers can have mold contamination.
Aseptic B/F/S-produced small-volume parenterals, such as
those used for local anesthetics, vitamins, vaccines and other standard injectable products, can be manufactured with
a twist-off-opening feature. They can also be combined
with a controlled-diameter form in the top to accommodate
needle-less spikes. Luer locks or luer-slip fits can also be
provided for making leak-free connections. For 2 to 5 mL
small volume parenterals, syringes can be connected directly to the ampoules without a needle, creating an inherently
safer packaging solution.
B/F/S-produced, one piece, plungerless sterile syringes
(designed for pre-filling) for use in flushing hospital equipment such as catheters, are available for replacing traditional two-piece plunger-type syringes. The B/F/S syringe
provides an offset chamber for trapping air, and preventing
it from being dispensed during drug delivery.
21

The increased focus on biologics, proteins and other complex solutions has brought B/F/S technology to the forefront. These pharmaceutical products often cannot withstand exposure to high temperatures for extended periods
of time without degradation of their active components,
making conventional terminal sterilization an unacceptable method to produce a sterile product. Temperature
sensitive biological and protein-based products can be
processed in advanced B/F/S machines, providing a level
of enhanced sterility assurance. Bulk sterilization, sterilization by gamma or e-beam irradiation, or filter sterilization
followed by direct packaging utilizing the B/F/S process
are used successfully for these types of products. B/F/S is
demonstrating less than a one-degree C temperature rise in
a liquid pharmaceutical which is packaged in a 5 mL polyethylene vial.
Advanced B/F/S technology can also include the application of insertion technology to permit the incorporation of a
sterile tip and cap insert into the Blow/Fill/Seal package to
produce a calibrated drop. This process enables increased
efficiency and sterility control in the processing of expensive drug formations for treatment of glaucoma and other
eye diseases. Other types of sterile inserts can be incorporated into the basic B/F/S-produced container as well. Top
geometrics for both bottles and ampoules can include a
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multientry rubber stopper or a controlled diameter injection-molded insert, useful where multiple administration
of a drug is required. Viscous products, with apparent
viscosities of less than 15,000 centipoise, and suspension
products can be handled by B/F/S machines with specially
designed product fill systems. These types of products use
innovative liquid-handling systems to maintain multiplecomponent products in a homogeneous solution during the
filling process. Basically, if the solution will flow and if it can
tolerate a minimum residence time, it can be packaged in
an advanced aseptic B/F/S machine.
The latest advanced models of aseptic B/F/S systems are
capable of manufacturing containers ranging in size from
0.2 mL to 1,000 mL at production rates of up to 15,000
units per hour. Pharmaceutical companies that use such
technological advances in aseptic B/F/S equipment design
and systems will realize the highest level of quality in the
production of their sterile liquid products. The ability to
provide these B/F/S systems, which must meet corporate,
scientific, regulatory and end-user requirements, can be a
quite demanding. These application challenges are being
met, however, by continuously evolving and improving
B/F/S system and container designs, driven by the need for
enhanced product integrity and
patient safety.
22

About Weiler Engineering:
Weiler Engineering is a worldwide provider of aseptic Blow/
Fill/Seal custom packaging machinery for pharmaceutical
and healthcare applications. Based in Elgin, Illinois, and
founded in 1959, Weilers proprietary Blow/Fill/Seal system
is the culmination of 40 years of innovation in machine design and sterile process development, producing a highly
advanced aseptic liquid packaging system. Its ASEPTECH Blow/Fill/Seal technology integrates blow molding,
sterile filling and hermetic sealing in one continuous operation to produce aseptically manufactured products.
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and end-user requirements. These application challenges

are met through the offering of several machine models
designed to manufacture containers ranging in size from 0.1
mL to 1,000 mL at production rates of up to 15,000 units per
hour, depending on container configuration.
To reach Weiler Engineering, please contact Chuck Reed;
1395 Gateway Drive, Elgin, Illinois 60124; Phone 847-6974900; email solutions@weilerengineering.com;
www.weilerengineering.com
The company uses the latest technological advances in

equipment design and systems to ensure the highest level of
quality in the production of sterile liquid products. Its equipment must meet demanding corporate, scientific, regulatory
23
Aseptic Blow/Fill/Seal: A Sustainable Process

for Packaging Pharmaceutical Liquids
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Aseptic Blow/Fill/Seal systems for packaging pharmaceutical liquids incorporate

materials and process that provide critical advantages for sustainable initiatives.
Sustainability is increasing in importance in all international markets. The pharmaceutical industry is no exception,
considering its environmentally taxing processes involving solvents, reagents, water and other agents. Along
with sterility assurance, process validation and regulatory
compliance, sustainability is becoming a more high-profile
component in pharmaceutical processing, and is considered a critical factor in the design of healthcare equipment, products and packaging.
The concept of sustainability has been a topic of interest
for many years, and has been more formally discussed and
considered since the late 1980s. Current international
focus has led to the development of regulatory guidance in
many of the worlds markets.
The United States Environmental Protection Agency has
posted the following definition of sustainability on its website www.epa.gov/sustainability/basicinfo.htm: Sustainability is based on a simple principle: Everything that we need
for our survival and well-being depends, either directly or

indirectly, on our natural environment. Sustainability creates and maintains the conditions under which humans and
nature can exist in productive harmony, that permit fulfilling
the social, economic and other requirements of present and
future generations.
The major emphasis with sustainable procedures in pharmaceutical manufacturing is directed to the reduction of
environmental impact, by decreasing consumption of raw
materials and energy usage in manufacturing and packaging processes, and by increasing the utilization of more
recycled materials.
There are many processes in pharmaceutical manufacturing that can be addressed to improve sustainability, and at
the same time reduce operating costs. One of the most
critically important objectives in
achieving sustainability is reducing process energy consumption.
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CONTINUED Aseptic Blow/Fill/Seal: A Sustainable Process

Implementing energy-efficient practices and technologies
should be a senior priority at the component, process and
system levels.
Energy monitoring systems and process control systems
are key tools that play an important role in energy management to reduce energy use. Such systems include metering, monitoring, and system controls such as integrated
programmable logic controllers (PLCs). These minimize
the time required to perform complex tasks and increase
efficiency in process operations. Such automated process
technologies that reduce energy consumption can also
improve product quality and consistency, and increase production throughput.
Embracing process sustainability and energy efficiency in the pharmaceutical industry is the aseptic Blow/
Fill/Seal (B/F/S) system for packaging pharmaceutical
liquids, which has made significant strides in achieving
sustainability objectives.
Aseptic B/F/S technology integrates the three-step process
of blow molding, sterile filling and hermetic sealing in one
continuous, highly-automated operation. Unique to aseptic
B/F/S systems compared to traditional aseptic processing
is their capability for rapid container closure and minimized
aseptic interventions.
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B/F/S is a self-contained process, where the raw materials

are virtually completely recyclable. The consolidation of
process steps through the use of B/F/S results in a significant reduction in the carbon footprint for the entire liquid
filling and packaging production process. The products
produced by aseptic B/F/S present a strong platform for
sustainability from a variety of perspectives.
Assessing Sustainability in Pharmaceutical Manufacturing
Pharmaceutical manufacturers possess a wide degree of
latitude in selecting and implementing systems for achieving environmental sustainability and energy efficiency. But
foremost is the necessity to have a structured methodology
that clearly delineates overall sustainability initiatives and
process improvements.
Two basic types of structured programs are available to
companies that manufacture pharmaceutical products: a)
programs that address multiple aspects of sustainability,
such as LEED (Leadership in Energy and Environmental Design), which provides a step-by-step process to achieve certification and recognition of having reached specific levels
of compliance; and, b) programs that provide assessment
and planning tools for reducing
energy consumption and plant
25

process costs. Both types of programs use a set of guidelines for evaluating the environmental impact involved
when manufacturing, packaging and distributing a product.
LEED is a certification program developed by the U.S.
Green Building Council (USGBC) that can be applied to any
building type and any building life cycle phase. It provides
a framework for identifying and implementing practical and
measurable green building design, construction, operations
and maintenance solutions.
LEED promotes a whole-building approach to sustainability by recognizing performance in key areas, such as sustainable sites, water efficiency, energy, materials, indoor
environmental quality, location and building design. The
programs internationally recognized green building certification system provides third-party verification that a
building was designed and built using strategies aimed at
improving performance across these metrics.
Although LEED certification does cover the actual physical facility and its habitable spaces, it does not provide
benchmarks for manufacturing and packaging processes
within the plant. For pharmaceutical manufacturers, whose
plant operations represent a significant energy draw which
sizably impacts their sustainability, a more process-orient-
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ed sustainability program would be needed to accurately

assess environmental impact.
Similar to LEED is Green Globes, operated by the Green
Building Initiative in the United States. Green Globes is a
building environmental design and management tool used
throughout the United States and Canada. It encompasses
both sustainability and energy management criteria, such
as integration of energy efficient systems, renewable energy, cogeneration and on-site wastewater treatment systems, in additional to sustainable environmental practices
such as sustainable site development and indoor air quality.
Green Globes delivers an online assessment protocol,
rating system and guidance for green building design,
operation and management for light industrial applications
like pharmaceutical manufacturing. But the program does
not govern industrial process which omits the significant
energy savings that can be achieved when taking these
processes into account.
The Building Research Establishments Environmental Assessment Method (BREEAM) is a leading European environmental program for building practices in sustainable
design. The program can assess
light industrial operations like
26

pharmaceutical plants, such as manufacturing, assembly
and packaging facilities both at the design stage and after
construction. Factors considered are energy management,
wastewater, land use, pollution, building materials, and
other sustainability factors. Credits are awarded in each of
the above areas according to performance. A set of environmental weightings then enables the credits to be added
together to produce a single overall score.
But like LEED and Green Globes, process assessment is not
covered in this program, which means it is an incomplete
assessment system for the sustainability requirements of
pharmaceutical manufacturers.
A program that does address process in pharmaceutical
plants is Energy Star, sponsored by the U.S. Department of
Energy (DOE), and administered through the Environmental
Protection Agency. Its program provides tools and resources to help improve the energy efficiency of manufacturing
and industrial facilities, including plant manufacturing and
packaging processes.
Energy Star supplies an energy guide specifically for the
pharmaceutical industry, which helps manufacturers evaluate potential energy improvement options, and develop action plans and checklists for the energy program. A major
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benefit is that it allows industrial companies to measure the

energy use of their facility, and to benchmark it with other,
similar facilities. Companies input key plant operating data
into an energy performance indicator to receive an efficiency score. It is a critical management tool for evaluating
how efficiently a plant is using energy compared to other
companies in their industry.
Also supporting energy efficiency in pharmaceutical processes is the DOEs Industrial Technologies Program (ITP),
run by the Office of Energy Efficiency and Renewable
Energy. This program addresses process functions in manufacturing plants that utilize steam, compressed air, process
heat, electric, and other systems that could potentially be
a source of wasted energy. It focuses on the reduction of
energy usage by integrating new technologies in industrial
controls, automation and robotics, and provides concrete
guidelines to achieve energy sustainability.
The ITP regularly conducts and makes available analytic
studies to identify energy-reduction opportunities within industrial processes, making these results available to
participant manufacturers. Application of the ITP program
has resulted in significant energy savings, waste reduction,
increased productivity, lowered
emissions and improved product
27

quality for U.S. industrial manufacturers.
Choosing the right program is critical to how quickly a
pharmaceutical manufacturers energy efficiency and sustainability goals can be achieved. A companys best strategy may be to utilize more than one of these programs.
A plant may decide to run with Energy Star or ITP for its
process energy improvements, while simultaneously going
with LEED or Green Globes for its other sustainability initiatives. Or, a manufacturer may choose to integrate state
energy efficiency programs with LEED, Green Globes or ITP
to capitalize on state energy credits or low interest loans
and grants that the states may offer for energy-efficient
solutions or equipment.
Life Cycle Analysis and B/F/S
The environmental performance of products and processes
in all industrial sectors, including pharmaceutical processing,
has become a key issue. To better determine how sustainable products and processes really are, life cycle analysis
(LCA) has emerged as a recognized instrument to assess the
ecological burdens and impacts connected with them.
A life cycle analysis is unique as a technique because it assesses environmental impacts associated with all stages of
a products life from cradle to grave. This includes from raw
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material extraction through materials processing, manufacture, distribution, use, repair and maintenance, and disposal or recycling. LCA can be used to find the most ecological way to improve product manufacturing, and can be a
useful decision-making tool for new products and process
development. It can also be used as a guide for the optimization of energy and raw material consumption.
Cradle-to-grave life cycle analysis, through mathematical
modeling, makes it possible to determine and manipulate
key metrics to provide a weighted average on total sustainability. Values for energy and resource consumption, the
extraction and processing of the raw materials, the pollution produced, recyclability and the effects of associated
transportation on the environment are applied in a numerical equation.
The weighted average then gives a clear evaluation of a
sustainable solution for the product and manufacturing/
packaging process being examined.
The LCA process is a systematic, phased approach and
consists of four components: 1) establishing the context
and parameters of the analysis; 2) an inventory, consisting
of an identification and quantification of energy, water and
materials usage and environmental releases; 3) an impact
assessment of these inventory
factors, and the potential human
28

and ecological effects; and 4) the different environmental
impacts are weighted relative to each other, then summed
to get a single number representing the total environmental impact.
An LCA allows a decision maker to study an entire product
system and its processes, thereby avoiding the sub-optimization that could result if only a single process were the
focus of the study.
In a comparison of different liquid pharmaceutical containers, for example, to determine which container had the
lowest releases to the environment and least affected the
supply of natural resources, an LCA would quantify the raw
materials used and the environmental loadings (including
energy consumption) from the manufacturing and packaging processes used to produce each container. Also viewed
would be comparative ecological impacts from distribution,
consumption and disposal or reuse of each container.
When selecting between two packaging processes, for example, it may appear that one is better for the environment
because it generates less chemical emissions at the point of
packaging. However, after performing an LCA, it could be
determined that the preferred process actually creates larger cradle-to-grave environmental impacts when measured
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across its influence on air, water and land. The packaging

process may use a film that is difficult or impossible to recycle. Therefore, the unselected process may now be viewed
as producing less cradle-to-grave environmental harm or
impact than the initial preferred technology.
From a life cycle analysis perspective, aseptic Blow/Fill/Seal
machines that provide packaging of pharmaceutical liquids
present much more streamlined and sustainable systems
for production of sterile products, compared to traditional
aseptic processing in a number of critical aspects:
Energy Management The most advanced aseptic B/F/S
systems are quite automated, compared to traditional
aseptic processing. These B/F/S machines are designed
to require minimum human access while operating in
Class-100 environments.
Various in-process control parameters utilizing the latest
generation of fully system-integrated PLCs, control and
monitor container weight, fill weight, wall thickness, isolation of visual defects and other factors, facilitating optimized system function.
These B/F/S machines allow very
efficient processing speed and
29

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short machine cycle times. Aside from the obvious improvement in throughput volume, they provide more efficient energy usage.
and used for other applications. The entire production and

recycle processes can be maintained on-site with minimal
need for off-site disposal of waste material.
According to the DOEs Energy Star program, implementation of monitoring and control systems, such as PLCs and
servo-drives, present well-documented opportunities for
energy savings.
Reduced Manual Interventions Waste reduction should

be viewed as an important objective in a sustainability
program. In aseptic packaging of pharmaceutical liquids,
waste can manifest itself in compromised quality, labor-intensive processes and reduced efficiency.
Recyclable Plastic Containers Aseptic B/F/S systems incorporate the use of recyclable plastic resins, as differentiated from glass containers used in traditional aseptic processing. Low-density polyethylene, high-density polyethylene
and polypropylene, used to produce aseptic containers for
injectables, ophthalmics, biologicals and vaccines are generally considered inert by the FDA. These inert materials
do not contain additives, have low water vapor permeability, and are easy and safe to handle in critical care environments such as hospitals.
These resins used in B/F/S processes are recyclable. Regulatory requirements permit reuse of the resin up to three
times before it must be discarded. As much as 50 percent
of the resin used in the B/F/S process can be reground and
directly used again within the process when mixed with virgin material. The remainder of the waste can be captured
Traditional aseptic procedures for packaging pharmaceutical liquids involves multiple steps in the handling and
manipulation of the material, containers and sterilization
filling processes with human intervention, and therefore
have a higher potential for contamination during processing. Additional processing steps for conventional aseptic
processing include receiving, inspection and warehousing
of incoming containers, washing and sterilizing of containers, separate processing steps and equipment for filling
and sealing, and end processing handling such as labeling.
The FDAs 2004 Guidance for Industry Sterile Drug Products
Produced by Aseptic Processing states that the design of
equipment used in aseptic processing should limit the number and complexity of aseptic
interventions by personnel.
30

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Both personnel and material flow should be optimized

to prevent unnecessary activities that could increase the
potential for introducing contaminants to exposed product,
container-closures or the surrounding environment.
dropper units for eye drop containers used to deliver a calibrated drop, are attached to the container after the blowing and filling process. These improvements streamline the
packaging process.
The latest generation of Blow/Fill/Seal machines, as exemplified in the ASEP-TECH B/F/S system from Weiler
Engineering, are highly automated, thereby severely reducing manual interventions. The forming, filling and sealing
steps are achieved in one unit operation the cycle being
completed within seconds. Such automation eliminates
unneeded manpower and reduces the risk to lessened
product integrity.
Changeover Flexibility When aseptic throughput is interrupted, or not running because of downtime, the entire
process line is affected, which represents a significant production loss to the manufacturer. Many B/F/S machines are
configured to produce more than one bottle shape or format. This makes it easy to change over from one container
size to another. A Blow/Fill/Seal machine might produce a
family of 2, 3 and 5ml, then switch to a family of 5, 10 and
15ml, or to one of 10, 15 and 20ml, moving from one to the
other with relative ease of machine set-up.
Elimination of Secondary Packaging B/F/S produced vials and bottles, by virtue of their opening features and simplified designs, such as twist-off tops, eliminate the need
for secondary packaging. Labeling is not needed, since
the molds can be engraved with product information. This
avoids an additional process step, and eliminates material
usage and the potential for additional waste generation.
Integrated Packaging of Inserts B/F/S allows pre-molded, pre-sterilized components, called inserts, to be integrated into the basic container. These inserts, including
items such as rubber and silicone stoppers, and tip-and-cap
B/F/S systems approach 99 percent uptime efficiency, significantly higher than traditional aseptic processing, which
is plagued with slow-downs and process interruptions in
part because of required manual interventions.
Embracing Sustainability
The Blow/Fill/Seal system improves product integrity and
better ensures patient safety over traditional aseptic processing procedures. As a result,
the United States Food and Drug
31

Administration and the United States Pharmacopoeia now
characterize modern B/F/S technology as an advanced
aseptic process, indicating its use as a preferred technology over other aseptic systems, and a better solution for the
sterile, aseptic processing of pharmaceutical liquids.
Waste reduction, resource and energy management, improved process controls and throughput efficiency are
key factors that have influenced the acceptance of aseptic
Blow/Fill/Seal. These are critical functions for achieving
sustainable practices in the packaging of aseptic pharmaceutical liquids. They save energy, increase productivity,
and reduce environmental impacts.
Advanced aseptic Blow/Fill/Seal technology has emerged
as an innovation in green technology within the pharmaceutical packaging sector. As government agencies and
pharmaceutical manufacturers steadily, but surely, embrace
the sustainability initiative, aseptic Blow/Fill/Seal technology will continue to occupy a prominent position in the
evolution of Green Processing.
Fill/Seal custom packaging machinery for pharmaceutical and healthcare applications. Based in Elgin, Illinois,
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and founded in 1959, Weilers proprietary Blow/Fill/Seal

system is the culmination of 40 years of innovation in machine design and sterile process development, producing a
highly advanced aseptic liquid packaging system. Its ASEPTECH Blow/Fill/Seal technology integrates blow molding,
are met through the offering of several machine models designed to manufacture containers ranging in size from 0.1 mL
to 1,000 mL at production rates of up to 15,000 units per
32
Improving Process Quality of Pharmaceutical

Liquids Aseptic Blow/Fill/Seal Technology
vs. Traditional Aseptic Processing
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Acknowledged by the FDA as an advanced aseptic process for the packaging of sterile pharmaceutical liquids,
blow/fill/seal technology is gaining increasing acceptance by providing a high assurance of product sterility,
eliminating the need for human intervention, improving flexibility in container design and increasing process uptime.
Since its introduction into the North American pharmaceutical market more than 40 years ago, blow/fill/
seal (B/F/S) aseptic processing has established itself
as a highly efficient and safe system for the filling and
packaging of sterile pharmaceutical liquids and other
healthcare products, such as creams and ointments.
B/F/S product usage has been widely established in
the ophthalmic and respiratory therapy markets for
some time, and lately B/F/S technology has been gaining increasing worldwide acceptance in the parenteral
drug marketplace, replacing traditional glass vial processing in a growing number of applications.
B/F/S enables a container to be molded from plastic,
aseptically filled and hermetically sealed in one continuous, integrated and automatic operation, without
human manipulation. The process provides flexibility

in container design and system changeovers, high volume product output, low operational costs and a high
assurance of product sterility. The inherent safety of
the process packaging sterile products under aseptic
conditions without human intervention has led the
FDA, and the United States Pharmacopoeia, to characterize B/F/S technology as an advanced aseptic
process, indicating its use as a preferred technology.
New advances in drug delivery, the desire to improve
convenience in handling pharmaceutical products,
growing emphasis on combination products, the
increasing focus on protein-based drugs and other biologics, and tighter regulatory
33
CONTINUED Improving Process Quality of Pharmaceutical Liquids

Aseptic Blow/Fill/Seal Technology vs. Traditional Aseptic Processing
criteria on product safety, have focused more attention
on B/F/S technology over traditional aseptic methods
as a better solution for the sterile, aseptic processing
of pharmaceutical liquids.
Traditional Aseptic Processing and
Sterility of Pharmaceutical Liquids
Microbial contamination is a serious issue for companies manufacturing liquid pharmaceutical formulations. Such liquids are ideal growth areas for bacteria
like Salmonella, E. coli and Staphylococcus, microbes
that have been found in various liquid drug products.
A supposedly sterile, but contaminated product may
result in deterioration of the drug and loss of potency,
pyrogenic reactions after administration to a patient
particularly in parenterals, infection of the patient
and colonization of microorganisms in the patient with
the risk of a secondary infection. Any microorganism,
pathogen or nonpathogenic, found in a supposedly
sterile pharmaceutical product is dangerous.
Drug manufacturers have pursued various methods of
sterilizing packaging components, product ingredients
and equipment in order to achieve a sterile product in
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its final form. One system used is traditional processing, followed by terminal sterilization, which involves
initially filling and sealing product containers within a
cleanroom environment. The environment is set up to
minimize the microbial content of the product while it
is being manufactured. Each component of the process the product, container and closure have a low
bioburden, but may or may not be sterile. The product, in the final container, is subjected to a terminal
sterilization process, such as heat or radiation. The
most common method uses autoclaving with saturated
steam under pressure.
Traditional aseptic processing allows a final sterile drug
product to be achieved by individually sterilizing the
containers, material and equipment in-process, resulting in a unified sterilized product. In traditional aseptic
processing, the containers are either supplied cleaned
and sterilized to the filling line, or they are cleaned and
sterilized within the aseptic filling line. Plastic containers are usually washed, dried, sterilized and cooled before filling. Glassware containers, which have been the
dominating packaging material for terminally sterilized and
34

traditionally sterilized pharmaceutical liquids, are usually sterilized in-line, exposed to hot air at 350 degrees
C while being passed through a Class 100 tunnel. A
glass container temperature of 180 to 200 degrees C is
adequate for achieving sterility.
Methods of sterilization used in aseptic processing include filtering the solution by dissolving it in a solvent,
such as Water For Injection (WFI), where the solution is
passed through a sterilizing filter or membrane. Filter
sterilization is used where the component is soluble
and likely to be adversely affected by heat. A variation
of this method includes subjecting the filtered solution
to aseptic crystallization and precipitation (Lyophilization) of the component as a sterile powder. Dry heat
sterilization is another effective method for sterilizing
components that are heat stable and insoluble. Irradiation can also be used to sterilize some components.
Aseptic processing handles components, materials and
equipment in such a manner that foreign microbial and
endotoxin contaminents that exceed pre-determined
acceptable levels, are not introduced to the product
stream. To this end, it is critical that all storage, con-
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veying, filling and container sealing stages be carefully controlled at each step of the process to maintain
sterility of the product. Traditional aseptic processing,
involving filling open glass bottles or vials, requires
that the manufacturer maintain aseptic conditions in
critical processing areas at all times. Unfortunately, the
majority of liquid drug product contamination over the
past several decades has come about from products
produced in traditional aseptic processing facilities.
Personnel Intervention inTraditional
Aseptic Critical Areas
Traditional aseptic sterilization involves handling and
manipulation of the material, containers, and sterilization filling processes with human intervention, and
therefore has a higher potential for contamination
during processing. The FDAs 2004 Guidance for Industry Sterile Drug Products Produced by Aseptic
Processing states that the design of equipment used in
aseptic processing should limit the number and complexity of aseptic interventions by personnel. Both
personnel and material flow should be optimized to
prevent unnecessary activities
that could increase the poten-
35

tial for introducing contaminants to exposed product,
container-closures or the surrounding environment.
Ordinary walking by a person emits roughly 10,000 skin
particles per minute. Such particles can and do hold
microbial contamination. A rip in a workers uniform, a
momentary exposed wrist, a mask placed too low on
the nose or physical contact with an open fill port will
increase microbial contamination within a critical area.
According to the FDAs guide, airborne contamination
is directly related to the number of people working in a
cleanroom and the level of congregation by personnel
in areas where critical aseptic manipulations are performed. Isolation of personnel from these critical areas
would eliminate the major source of contamination in
traditional aseptic processing.
In traditional aseptic processing, changing or adjusting
filling nozzles and heads necessitates the shutdown of
the filling operation and requires re-sterilization of the
entire equipment. This increases manual intervention
in this critical area. Cleaning and sterilization which is
carried out by personnel, opens the door to breaching
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of established procedures for microbial decontamination and potential introduction of other particulates
like dirt, oil and chemicals.
Mold is common flora found on floors, walls and ceilings of buildings. Contamination occurs due to the
retention of water in cracks, edges and joints that are
susceptible because of inadequate sealing. Brooms,
mops and anything used for cleaning can become
contaminated and increase atmospheric contamination
because of raised dust or splashing water. In traditional aseptic processing, significant manual intervention
is required in critical areas to maintain compliance with
established sterile mandates.
Advanced Blow/Fill/Seal Aseptic Technology
In advanced aseptic B/F/S processing, containers are
formed from a thermoplastic granulate, filled with a
liquid pharmaceutical product and then sealed within a
continuous, integrated and automatic operation without human intervention.
Bulk solution prepared under
low bioburden or sterile con-
36

ditions is delivered to the machine through a product
delivery system that has been previously sterilized
using an automated steam-in-place process.
Modern B/F/S machines are fully automated, designed
to require minimum human access and operate in a
classified environment using the following steps: (a)
granules of a polymer resin, conforming to a predetermined set of specifications, such as polyethylene, polypropylene, co-polymers or other blow-moldable resins,
are pneumatically conveyed from a non-classified area
into the hopper of the B/F/S machine, from which the
plastic is fed into a multi-zone rotating screw extruder
which produces a sterile homogenous polymer melt
(160250 degrees C); (b) then to a parison head which
produces hollow tubular forms of the hot resin (called
parisons). The parisons are prevented from collapsing
by a stream of sterile filtered support air. Some highspeed B/F/S machines have up to sixteen parisons being formed simultaneously; (c) container mold(s) close
around the parisons, and the bottom of the parison is
pinched closed, while the top is held open in a molten
state; (d) the container is formed in the mold by blowing sterile air or creating a vacuum; (e) filling needles
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deposit the stipulated volume of product into the

container; (f) the filling needles are withdrawn, and the
upper part of the mold closes to form and seal the upper part of the B/F/S container; (g) the mold is opened
and the completed, filled containers are conveyed out
of the B/F/S machine to a remote station where excess
plastic is removed and the finished product is then
conveyed to final packaging.
Various in-process control parameters, such as container weight, fill weight, wall thickness and visual defects
provide information that is monitored and facilitates
ongoing process control.
The forming, filling and sealing steps are achieved
in one unit operation the cycle being completed
within seconds. Automation of B/F/S process steps
eliminates manual intervention and reduces risk to the
product. No production personnel are present in the
filling room during normal operation.
37

Microbial and Particulate Integrity
in the Aseptic Blow/Fill/Seal System
Sterility of B/F/S polymeric containers, materials and
processes is validated by verifying that time and temperature conditions of the extrusion, filling and sealing
processes are effective against endotoxins and spores.
Challenge studies have been conducted on the sterility levels of advanced B/F/S technology, which
demonstrate a uniform capability of achieving
contamination rates not exceeding 0.001 percent
throughout the entire process. Even higher sterility
assurance levels, approaching 0.000001 percent, have
been achieved using high levels of airborne microbiological challenge particles.
Endotoxins are a potential pyrogenic contaminant, essentially dead bacterial cellular matter. They can lead
to serious reactions in patients, particularly with those
receiving injections, ranging from fever to death. A
critical aspect of B/F/S technology is its pyrogen-free
molding of containers and ampoules. Extensive experiments confirming the efficacy of the B/F/S extrusion
process have been performed using high levels of
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spores and endotoxin-contaminated polymer granules.

The typical B/F/S extruders have demonstrated spore
contamination rates of 0.000001 percent, and 0.00001
percent for endotoxins.
Control of air quality is critical for sterile drug product manufacture. B/F/S equipment design typically
employs the use of specialized measures to reduce
microbial contamination and particle levels that can
contaminate the exposed product. The B/F/S process inherently produces a very low level of particulate
matter and much of potential B/F/S microbial contamination (viable) in the air is mitigated by the absence
of manual intervention in its critical areas. Non-viable
particles generated during the plastic extrusion, cutting, and sealing processes are controlled. Provisions
for carefully controlled airflow protect the product by
forcing created particles outward while preventing any
inflow from the adjacent environment. These zones
of protection can also incorporate designs that separate them from the surrounding environment, providing additional product protection.
38

The B/F/S critical processing zone is continually supplied with HEPA-filtered air by an air shower device
(shroud). The B/F/S critical zone is the area where
the containers are exposed during filling. Air in the
critical zone meets Class 100 (ISO 5) microbiological
standards during operations. The critical zone is continuously monitored to ensure a positive differential
pressure is maintained between the shroud and the
adjacent cleanroom.
Plastic vs. Glass Containers
Injectables, ophthalmics, biologicals and vaccines are
produced in a number of different types of containers,
including bottles, vials and ampoules that are made
from glass and plastic. Protecting the contents of
these aseptic liquid drugs through filling, packaging
and transportation, and allowing for safe and easy
administration are critical objectives in the aseptic
process. The industry is infused with a strong quality
control emphasis. Raw materials, and in-process and
finished products are continually checked for approval
and rejection.
The packaging needs for pharmaceutical liquids are
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quite demanding. It is not unusual for degradation

of the product to occur during processing or while in
transit. The physical properties of liquids can be altered with inadequate packaging components. For
aseptic filling, the package must be produced, stored,
filled and sealed under conditions that preserve sterility. Likewise, the appearance of particulates in sterile
solutions is equally undesirable.
Glass, although a standard in the aseptic pharmaceutical liquids industry, is not without its limitations. There
is the safety issue glass vials are subject to breakage,
both in transit and while being administered. Handling
glass containers always involves a certain amount of
risk of lacerations and glass splinters. Glass ampoules,
for example, generate a fine array of small glass particles during opening.
Manufacturers using glass containers are also subjected to design limitations when the designs become
somewhat complex. With glass containers, as design
complexity increases so does the cost. Once glass
containers are produced,
they need to be transported
39

to the aseptic facility. Glass is typically transported in
cardboard boxes that can contain mold spores, such as
Penicillin sp. and Aspergillus sp., as well as bacteria like
Bacillus sp. Paper, also used in the shipping of glass,
can also contain mold spores. The rubber closures used
on the glass containers can have mold contamination.
Domestic drug companies have been slow to change
to plastic, primarily due to the existing installed base
of glass production of small-volume parenteral drugs
in the United States. However, the same is not the
case with new drugs that are coming onto the market. These are more frequently being looked at, and
submitted for FDA approval, in plastic containers produced by advanced B/F/S aseptic processing. Supporting this move is that the B/F/S processing resins,
polyethylene and polypropylene, are generally considered inert by the FDA. Many of the blow molding
resins used in B/F/S processing have received international acceptance as suitable for food and drug applications, and many of the drug products produced
outside of the United States can be found packaged
with these resins.
With the continued refinement of BSF technology, its
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acknowledgment by the FDA as a preferred technology for aseptic processing, and its growing acceptance
by drug companies, the migration from glass to plastic
containers used for aseptic pharmaceutical liquids is
growing rapidly. It has become more cost effective
to use plastic containers for aseptic liquids, which
effectively costs manufacturers one-third of the cost
of glass. Plastic is less expensive to ship because the
containers are lighter. For small-volume parenterals,
the use of plastic is inevitable, and increasingly being
considered for these reasons.
Although many B/F/S systems make available only a limited number of container choices within each container
category, some B/F/S machines do allow for broad versatility in container design. Advanced B/F/S machines
can design virtually any container mold through the use
of sophisticated CAD/CAM technology and 3-D modeling. These design systems, when interfaced with the
latest in CNC and EDM machinery, ensure fabrication of
key components to precise tolerances.
B/F/S machine designs also
allow for mounting of sepa-
40

rate sterile items (inserts) within the B/F/S container,
and in-mold coding and engraving, which provide
further opportunities for innovative design over that
of glass products.
Flexibility with Changeovers Allows Shorter Runs,
Increased Uptime, Maximized Throughput
Modern B/F/S system design is focused on simplicity
and flexibility. Many B/F/S machines are configured to
produce more than one bottle shape or format. This
makes it easy to change over from one container size
to another. A B/F/S machine might produce a family of
2, 3 and 5ml, then switch to a family of 5, 10 and 15ml,
or to one of 10, 15 and 20ml, moving from one to the
other with relative ease of machine set-up. This is
ideal for manufacturers performing contract packaging
of aseptic liquid pharmaceutical solutions, because of
their need for changeover flexibility.
The growing usage of biologics is demanding packaging
in different formats. They usually require smaller process
runs and are typically heat sensitive. Many of these new
biotechnological drugs do not withstand steam sterilization or irradiation and so are best treated aseptically.
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More advanced B/F/S machines have been designed so

they can handle these heat sensitive products.
Machine models are available that can produce containers ranging in size from 0.1mL to 1000mL at production rates of 15,000 units per hour, depending on
container configuration.
B/F/S machine efficiency is very high. More advanced
B/F/S machines can approach 99 percent uptime efficiency, which is significantly higher than traditional
aseptic processing which is plagued with slow-downs
in part because of manual interventions. To further
minimize potentials of system downtime, some manufacturers are now segmenting their high-volume process lines into more short-run lines, in the event that if
one of the lines goes down for maintenance or repair,
it will not stop the entire production throughput.
When aseptic throughput is interrupted, or not running
because of downtime, the entire process line is affected, which represents a significant production loss to
the manufacturer.
41

An Aseptic Technology Destined to Prevail
More rapid container closure processing, elimination
of aseptic critical-area personnel interventions, increased system uptime over traditional processing,
pyrogen-free molding of containers and ampoules,
more flexibility with container design, and an increased
capability to capitalize on short runs these are some
of the benefits for manufacturers inherent in advanced
blow/fill/seal aseptic technology. And for consumers,
increased safety and confidence in their drug products.
These are advances that are significant, if not fully realized yet within the aseptic liquid pharmaceutical marketplace. But it is apparent that advanced B/F/S aseptic technology is destined to become a major player in
this arena.
Weiler Engineering is a worldwide provider of aseptic
blow/fill/seal custom packaging machinery for pharmaceutical and healthcare applications. Based in Elgin,
Illinois, and founded in 1959, Weilers proprietary
blow/fill/seal system is the culmination of 40 years of
innovation in machine design and sterile process de-
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velopment, producing a highly advanced aseptic liquid packaging system. Its ASEP-TECH blow/fill/seal
technology integrates blow molding, sterile filling and
hermetic sealing in one continuous operation to produce aseptically manufactured products.
The company uses the latest technological advances in equipment design and systems to ensure the
highest level of quality in the production of sterile
liquid products. Its equipment must meet demanding
corporate, scientific, regulatory and end-user requirements. These application challenges are met through
the offering of several machine models designed to
manufacture containers ranging in size from 0.1mL to
1000mL at production rates of up to 15,000 units per
To reach Weiler Engineering, please contact Chuck
Reed; 1395 Gateway Drive, Elgin, Illinois 60123; Phone
847-697-4900; email solutions@weilerengineering.
com; www.weilerengineering.com
42
Improving Uptime in Aseptic Processing of

Pharmaceutical Liquids with Blow/Fill/Seal
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Maximized uptime, minimized changeover time and efficient OEE are key factors that have
influenced the acceptance of aseptic Blow/Fill/Seal in the packaging of pharmaceutical liquids.
Pharmaceutical manufacturers, for many years, have experienced exceptional growth with the development of new
drugs and the marketing of these products, but pharmaceutical manufacturing processes have historically lagged behind
in efficiency compared to those of other consumer product
industries. Within the past decade, however, responding to
changes in consumer purchasing such as the influence of the
Internet, stiffer guidelines from the Food and Drug Administration and other regulatory agencies, and significantly increased costs to bring new drugs to market, drug companies
have had to take a closer look at their manufacturing processes to make them more efficient, to stay competitive.
A key factor to reaching high levels of efficiency in pharmaceutical manufacturing is maintaining uptime, which has
always been of critical importance to manufacturers in every
industry. When throughput is interrupted, or not running
because of downtime or changeovers, the entire process
line is affected, which can present a significant production
loss to the pharmaceutical manufacturer.
Overall Equipment Effectiveness

An important tool that pharmaceutical manufacturers are
using to increase uptime, and measure and improve line
efficiency is Overall Equipment Effectiveness (OEE). OEE
measurement is also frequently used as a key performance
indicator (KPI) in conjunction with lean manufacturing efforts to provide an indicator of success.
Overall Equipment Effectiveness (OEE) is a system of analytics to determine how effectively a manufacturing operation is utilized. It identifies and quantifies the performance
of specific areas of a manufacturing line to bring about process improvement. OEE is determined by factoring three
key metrics of machine and line operation: 1) availability; 2)
performance; and 3) product quality.
Availability represents the percentage of scheduled time that
the process is available to op-
43
CONTINUED Improving Uptime in Aseptic Processing

of Pharmaceutical Liquids with Blow/Fill/Seal
erate. Also referred to as uptime. Factors like equipment
cleaning, changeovers, equipment breakdown and preventative maintenance are conditions that will influence the
OEE metric rating for Availability.
Performance represents the speed at which the process or
machine runs as a percentage of its designed speed. Factors that influence the OEE rating for Performance include
temporary equipment stops from jams, machine cycle settings, designated speed and product throughput.
Quality in the OEE metric represents the good products
produced as a percentage of the total units started. This
OEE rating is influenced by rejected products. More specifically, those rejects caused by equipment or personnel, and
those rejects separated into rework and scrap.
Each of these metrics are then factored at a percentage of
operation compared to the ideal operating condition. For
example, a given line may have an Availability factor of 86.7
percent, a Performance rating of 93.0 percent, and a Quality factor of 95.0 percent. The OEE would then be computed by multiplying 86.7% x 93.0% x 95.0%, for a composite
OEE metric of 76.6 percent for that line.
Typically, each metric would factor in many pieces of equip-
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ment and operating aspects of the pharmaceutical line

to arrive at a percentage. In pharmaceutical packaging
these machines may include sorters, fillers, cappers, labelers, cartoners, case packers and palletizers. Each machine
would have its own systems and cycles. An OEE rating can
be determined for each machine on the line, and/or for the
entire line.
Blow/Fill/Seal Processing of
Aseptic Pharmaceutical Liquids
One area of pharmaceutical manufacturing that has made
significant gains in Overall Equipment Effectiveness is in the
packaging of aseptic pharmaceutical liquids with Blow/Fill/
Seal (B/F/S) technology. From the perspective of OEE, and
focusing on uptime and changeover time improvement,
aseptic Blow/Fill/Seal machines present highly efficient systems for production of sterile liquid products.
The aseptic Blow/Fill/Seal system has proven to improve
product integrity and better ensure patient safety over
traditional aseptic processing procedure. As a result, the
United States Food and Drug Administration and the United States Pharmacopoeia now characterize modern B/F/S
technology as an advanced aseptic process, indicating its
use as a preferred technology
over other aseptic systems, and
44

a better solution for the sterile, aseptic processing of pharmaceutical liquids.
B/F/S is a self-contained process. The consolidation of process steps results in streamlined efficiency for the entire liquid filling and packaging production process. The technology integrates a three-step process of blow molding, sterile
filling and hermetic sealing in a continuous, highly-automated operation. Unique to aseptic B/F/S systems compared
to traditional aseptic processing is their capability for rapid
container closure and minimized aseptic interventions. Further, B/F/S incorporates the use of recyclable plastic resins.
Low-density polyethylene, high-density polyethylene and
polypropylene, used to produce aseptic containers for injectables, ophthalmics, biologicals and vaccines are generally considered inert by the FDA.
Simplified B/F/S Machine Design Improves Uptime
Traditional aseptic procedures for packaging pharmaceutical liquids involve multiple steps in the handling and manipulation of the material, containers and sterilization filling
processes with human intervention, and therefore have
a heightened potential for system downtime and product contamination during processing. Manual processing
steps for conventional aseptic processing include receiving,
inspection and warehousing of incoming containers, wash-
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ing and sterilizing of containers, separate processing steps

and equipment for filling and sealing, and end processing
handling such as labeling.
In pharmaceutical processing, it is the filling process that
determines the line speed. System delays and downtime
caused by such manually-dependent processes in aseptic
packaging can have significant throughput and cost consequences which depress OEE.
Conversely, automating the aseptic process can have a
sizable impact on improving uptime. The most advanced
aseptic B/F/S systems are quite automated, compared to
traditional aseptic processing. These B/F/S machines are
designed to require minimum human access while operating in Class-100 environments. Various in-process control
parameters utilizing the latest generation of fully-system-integrated PLCs, control and monitor container weight, fill
weight, wall thickness, isolation of visual defects and other
factors, facilitating optimized system function.
With the latest generation of Blow/Fill/Seal machines, as exemplified in the ASEP-TECH B/F/S system from Weiler Engineering, the forming, filling and sealing steps are achieved
in one unit operation the cycle
being completed within seconds.
45

Such automation eliminates unneeded manpower and reduces the risk to product integrity. These B/F/S machines allow very efficient processing speed and short machine cycle
times. They minimize the time required to perform complex
tasks and increase efficiency in process operations. Such automated process technologies improve product quality and
consistency, and increase production throughput, substantially supporting Overall Equipment Effectiveness.
Flexibility of B/F/S Container Design
Optimizes Machine Operation
B/F/S allows considerable flexibility in the design of containers, adding to improved OEE. Pre-molded, pre-sterilized components, called inserts, can be easily integrated
into the basic container. These inserts, including items such
as rubber and silicone stoppers, and tip-and-cap dropper
units for eye drop containers used to deliver a calibrated drop, are attached to the container after the blowing
and filling process, prior to sealing. These improvements
streamline the packaging process, eliminating the need for
secondary packaging. Labeling is not needed, since the
molds can be engraved with product information, which
avoids an additional process step.
Advanced aseptic B/F/S containers and ampoules can be
manufactured to deliver precise dosing in disposable for-
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mats. The incorporation of a sterile tip-and-cap, a rubber

stopper or a multi-entry insert into the B/F/S package offers
added flexibility in container design and drug delivery
methods, as well as enhanced sterility safety.
Quick Changeovers
Packaging equipment changeovers present one of the most
costly and time-consuming activities within pharmaceutical
manufacturing. Indeed, changeover adaptability remains
the most critical packaging machine feature, with sizable influence on OEE. The versatility of packaging equipment to
facilitate rapid changeovers has never been more important
in pharmaceutical manufacturing, and aseptic Blow/Fill/Seal
systems exemplify this initiative.
Many B/F/S machines are configured to produce more than
one bottle shape or format. This makes it easy to change
over from one container size to another. A B/F/S machine
might produce a family of 2ml, 3ml and 5ml containers,
then switch to a family of 5ml, 10ml and 15ml containers,
or to one of 10ml, 15ml and 20ml containers, moving from
one to the other with relative ease of machine set-up.
This is ideal for manufacturers, such as those performing
contract packaging of aseptic liquid pharmaceutical solutions, because of their need for
changeover flexibility. ASEP-
46

TECH B/F/S systems from Weiler are capable of producing containers ranging in size from 0.1ml to 1,000ml at
production rates of 15,000 units per hour, depending on
container configuration.
The growing usage of biologics is demanding packaging
in different formats. These drug products usually require
smaller process runs and are typically heat sensitive. Many
of these new biotechnological drugs do not withstand terminal sterilization with steam or irradiation, and so are best
treated aseptically. More advanced B/F/S machines are
designed so they can handle these heat sensitive products
without adversely affecting product quality.
The B/F/S process offers outstanding versatility for multiple container designs. A unique design feature offered on
the ASEP-TECH B/F/S systems, for example, permits the
insertion of a secondary delivery device into the container
prior to the final hermetic sealing step. This feature can be
suspended, however, without requiring significant equipment changeover. This allows the production of standard
containers without inserts on the same machine with only a
simple recipe and tooling change.
To further minimize potentials of system downtime, some
pharmaceutical manufacturers are now segmenting their
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high-volume aseptic process lines into multiple, smaller

Blow/Fill/Seal lines. The use of smaller machines provides
enhanced production flexibility and improved efficiency. In
the event that one of the lines goes down for maintenance
or repair, it will not stop the entire production throughput.
Products can be easily campaigned with B/F/S, using one
line with one container geometry for multiple products.
Since B/F/S is ideally suited for these campaigns due to
quick changeovers, it is a natural pick for manufacturers
desiring to optimize OEE.
Efficient Utilization of Time
Modern B/F/S system design embodies OEE initiatives,
being focused on changeover simplicity and flexibility, and
permitting shorter runs, increased uptime and maximized
throughput.
Blow/Fill/Seal machine efficiency rates very high. More
advanced Blow/Fill/Seal machines can approach 99 percent uptime efficiency, significantly higher than traditional
aseptic processing, which is plagued with slow-downs, in
part because of manual interventions. B/F/S also performs
noticeably higher than the peak 70 percent operating
efficiency of the worlds most streamlined pharmaceutical
manufacturing facilities.
47

Improved uptime, minimized changeover time and efficient
OEE are key factors that have influenced the acceptance
of aseptic Blow/Fill/Seal. These are critical functions for
achieving improved product quality and profitability in the
packaging of aseptic pharmaceutical liquids.
is the culmination of 40 years of innovation in machine
design and sterile process development, producing a
SPONSORED BY
BACK TO EBOOK

equipment design and systems to ensure the highest level
of quality in the production of sterile liquid products. Its
equipment must meet demanding corporate, scientific,
regulatory and end-user requirements. These application
challenges are met through the offering of several machine
models designed to manufacture containers ranging in size
from 0.1 ml to 1,000 ml at production rates of up to 15,000
units per hour, depending on container configuration.
48
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Streamlined Blow/Fill/Seal Insertion

Technology Increases Flexibility and Safety in
Aseptic Packaging of Pharmaceutical Liquids
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Isolators adapted specifically for Blow/Fill/Seal insertion applications separate, but connected to the B/F/S
unit permit sterile placement of tip-and-cap inserts into plastic metered-dose containers, and rubber/silicone
single- and multi-entry stoppers into parenterals, while operating within a dedicated Class 100 environment.
by Andrew W. Goll, Technical Sales Manager, Weiler Engineering, Inc.
The aseptic Blow/Fill/Seal (B/F/S) process has proven
to be an ideal system for the creation of a wide variety of container shapes and sizes used for packaging
sterile pharmaceutical liquids. B/F/S is well suited to
producing closed aseptic containers, like injectable
products, that need to be opened under critically
sterile conditions within a clinical environment such as
a hospital, as well as sterile products opened by individuals in work-a-day environments like ophthalmic
dropper units. These products must meet the mandates of drug manufacturers and government regulators that require sterile products that will stay sterile
until the time of use. Manufacturers also desire the
most cost-efficient packaging systems to achieve these
ends without any loss of product integrity. One of the
more recent improvements in aseptic B/F/S processing
that facilitates these goals is the advance in insertion

technology. The latest generation of aseptic B/F/S
machines incorporates dedicated isolators adapted
specifically for insertion applications. These modular
insertion isolators are typically located outside of the
classified machine room, separate from but directly
connected to the B/F/S unit through a transfer tunnel.
The isolator and tunnel are typically sterilized with
vaporized hydrogen peroxide and the Class 100 environment within it is maintained by HEPA filtration. This
new addition to the aseptic B/F/S system has not only
streamlined the insertion process, but has provided a
higher level of sterility assurance for products with tipand-caps and rubber/silicone
stoppers inserted under aseptic conditions.
49
CONTINUED Streamlined Blow/Fill/Seal Insertion Technology Increases

Flexibility and Safety in Aseptic Packaging of Pharmaceutical Liquids
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Insertion Applications in Advanced Aseptic B/F/S

Although glass has been the traditional choice for
packaging sterile pharmaceutical liquid products,
B/F/S-produced plastic containers have emerged as
a viable alternative during the past few decades, and
particularly with the recognition by the U.S. Food and
Drug Administration of B/F/S as an advanced aseptic
process, indicating it as a preferred technology over
other aseptic systems.
molding resins used in B/F/S processing have received

international acceptance as suitable for pharmaceutical liquids applications. These inert materials do not
contain additives, have low water vapor permeability,
and are easy and safe to handle in critical care environments such as hospitals. Further, temperature-sensitive biological and protein-based products can be
processed in advanced B/F/S machines, providing a
level of enhanced sterility assurance.
Unlike glass, plastic containers are shatter-proof. Glass

vials are subject to breakage, both in transit and while
being administered. Handling glass containers always
involves a certain amount of risk of lacerations and
glass splinters, such as with small volume parenterals,
where glass ampoules can generate a fine array of
small glass particles during opening.
For these reasons the interest in B/F/S-produced plastic containers, and particularly injectable product containers, is continuing to grow within the pharmaceutical industry.
A critical aspect of B/F/S technology is its pyrogen-free molding of containers and ampoules. B/F/S
processing resins, polyethylene and polypropylene,
used to produce aseptic containers for injectables,
ophthalmics, biologicals and vaccines are generally
considered inert by the FDA, and many of the blow
Along with the growing interest in B/F/S plastic containers, the application of aseptically-produced B/F/S
containers with inserts has also become increasingly
popular. Advanced B/F/S machine designs allow the
capability to incorporate the addition of pre-molded,
pre-sterilized components (inserts) into the basic container. These inserts, including items such as rubber
and silicone stoppers, and tipand-cap dropper units for eye
50
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drop containers (used to deliver a calibrated drop), are
attached to the container after the blowing and filling
process, prior to final sealing step. The application of
inserts has allowed B/F/S technology to advance and
expand into product markets which were previously
unavailable, such as intravenous drug administration,
solution irrigation and ophthalmic dropper units.
With ophthalmics, the B/F/S insert process enables
increased efficiency and sterility control in the processing of expensive drug formations for treatment
of glaucoma and other eye diseases. Other types
of sterile inserts can be incorporated into the basic
B/F/S-produced container as well, such as top geometrics for both bottles and ampoules that can include
a multi-entry rubber stopper or a controlled diameter
injection-molded insert, useful where multiple administration of a drug is required. The stopper would
typically be an FDA-approved, rubber or silicone insert
that would be placed inside the bottle or parenteral.
Then, at the point of delivery the nurse would stick a
needle through the stopper and extract the fluid, or if
it is a vascular flush, the nurse would insert it into the
patients IV set.
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Aseptic B/F/S-produced small-volume parenterals (SVP),

such as those used for local anesthetics, vitamins, vaccines
and other standard injectable products, can be manufactured with a twist-off-opening feature. They can also be
combined with a controlled-diameter form in the top to
accommodate needle-less spikes. Luer locks or luer-slip fits
can also be provided for making leak-free connections. For
2 to 5 mL small- volume parenterals, syringes can be connected directly to the ampoules without a needle, creating
an inherently safer packaging solution.
B/F/S-produced, one piece, plungerless sterile syringes
(designed for pre-filling) for use in flushing hospital equipment such as catheters, are available for replacing traditional two-piece plunger-type syringes. The B/F/S syringe
provides an offset chamber for trapping air, and preventing
it from being dispensed during drug delivery.
Advanced B/F/S insertion processes can also incorporate
tamper-evident features for multi-dose container closures,
offering added security.
Advanced Insertion Isolation Technology
The latest generation of Blow/Fill/Seal machines use a
modular design, integrating duo
Class 100-environment manu-
51

facturing processes, and utilizing servo-drive controls with
system-integrated PLCs (programmable logic controllers).
These B/F/S systems address process monitoring, streamlined maintenance and consolidated machine components
for optimum performance.
They feature advanced insertion technology, incorporating the use of a Class 100 environment isolation chamber
located outside of the B/F/S unit, but integrated with the
B/F/S machine. This process allows the operator to present a pre-sterilized (typically with a gamma or an e-beam
process) component (stopper or dropper insert) through a
secure sterile pass-through into a Class 100 environment for
insertion within the B/F/S filling shroud.
Sterile inserts are loaded into the isolator through a double-locking, sterile rapid transfer port. The inserts are indexed into a special track mechanism which transfers them
from the isolator into the nozzle shroud of the B/F/S. The
filling of the container and the placement of the insert into
the container both take place in sequential operations within
the nozzle shroud. Each component is inserted into a molded container before the final top closure is formed. The
container-insert combination package is then sealed, having
given the B/F/S product the intended drug delivery features.
The entire operation takes place under Class 100 controlled
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environment conditions with no human intervention, providing a high level of sterility assurance for the final product.
Key factors of this isolation technology include minimizing particles generated through moving components, and
controlling the air pressure cascade from the isolator to the
nozzle shroud, providing enhanced sterility assurance and
thereby achieving regulatory compliance. All of the mechanical features required to get the inserts from the isolator into the B/F/S container are enclosed within a Class 100
environment. A servo-controlled fill and insertion system
eliminates the need for hydraulics above the mold. Servo-drives deliver the inserts, so belt and chain mechanisms,
which typically require lubrication and can generate non-viable particles, are eliminated. High-speed PLCs provide
integrated control architecture for the entire B/F/S machine. All modular functionality, such as with the insertion
isolator, the insert-delivery track system and the B/F/S filling
processes are totally integrated for speed and optimum
performance. The PLCs receive continuous communication
from the B/F/S-isolator system, continually monitoring the
differential air pressure in the B/F/S and isolation systems,
as well as ensuring that particle counts are under control.
Conventional liquid aseptic
manufacturing, with parenterals
52

for example, requires filling and sealing to be carried out
in a Class 100 environment and necessitates considerable
validation efforts. Both the B/F/S machine and the insertion isolator do not need to be housed in a Class 100 area
because their activities are protected within the machines
themselves. This protection considerably reduces the
scope of validation requirements.
Sterility and particulate matter are two of the most critical requirements for aseptically-produced products, and advanced
B/F/S and insertion isolation technology offer distinct advantages over earlier systems. This includes maintaining precise
control over differential air pressure between the isolator,
the insert transport and the B/F/S nozzle shroud. Both the
isolator and the B/F/S system are equipped with HEPA air
showers to assure a Class 100 environment under dynamic
conditions in the isolator, tunnel and nozzle shroud area.
It has been well documented that in the B/F/S process,
non-viable particles primarily originate from the electrically heated cut-off knife contacting the molten parison, and
that better control of non-viable particulates will provide
enhanced sterility assurance for the Blow/Fill/Seal process.
The more advanced B/F/S systems use additional technology in response to FDA concern over particulate contamination during B/F/S fabrication.
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Ultrasonic KleenKut technology can be used to cut the

molten parison at ambient temperature, drastically reducing non-viable smoke particles that are generated by traditional hot knife cutting. The process reduces particulates in
the cutting area by 99 percent. Non-viable particles 0.3m
to 10m in size are significantly reduced in quantity compared with the volume of particles produced during the use
of hot-knife cut-off mechanisms.
Expanding Use of Blow/Fill/Seal Insertion Technology
Advanced aseptic B/F/S containers and ampoules can deliver precise dosing in disposable formats. The incorporation of a sterile tip-and-cap, a rubber stopper or a multi-entry insert into the B/F/S package offers added flexibility
in container design and drug delivery methods, as well as
enhanced sterility safety. These benefits are continuing to
push the acceptance and use of advanced aseptic B/F/S
technology, particularly into injectable product areas and
biologics where proteins and other complex solutions
have brought B/F/S technology to the forefront.
The B/F/S process offers outstanding versatility for multiple
container designs. A unique design feature of the ASEPTECH B/F/S systems, for example, permits the insertion
process to be suspended without
requiring significant equipment
53

changeover. This feature allows the production of standard
containers without inserts to be produced on the same machine with a simple recipe change.
As the use of advanced aseptic Blow/Fill/Seal processes
broaden, insertion technology will become more important
as drug producers continue to seek new delivery methods
for breakthrough drugs.
About the Author:
Andrew W. Goll is Technical Sales Manager for Weiler Engineering, Inc., responsible for technical support for the companys customers worldwide. He has over 18 years of experience in the Blow/Fill/Seal community including research
and development, design engineering, and contract and
generic manufacturing plant operations. He is a member
of the Parenteral Drug Association (PDA) and International
Society for Pharmaceutical Engineering (ISPE). Goll holds a
Bachelor of Science degree in business administration and
a Master of Business Administration degree.
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is the culmination of 40 years of innovation in machine

design and sterile process development, producing a
are met through the offering of several machine models designed to manufacture containers ranging in size from 0.1 mL
to 1,000 mL at production rates of up to 15,000 units per
To reach Weiler Engineering, please contact Chuck Reed,
Director, Sales & Marketing; 1395 Gateway Drive, Elgin,
Illinois 60124; Phone 847-697-4900;
email solutions@weilerengineering.com;
54

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Historical/Current Regulatory Viewpoint

What kind of containers may be produced?

B/F/S Inspiration Image Gallery

Drivers Affecting Innovation and the Use of B/F/S for

Resin Choices/Examples of Container Cost Savings

Limit Human Intervention and Effectively Reduce Airborne Microbial

Current Regulatory Viewpoint

Considered an advanced aseptic technology when operated properly

When the parison

The fill assembly

The mold opens and

What kind of containers may be produced?

CLICK THROUGH THE NEXT 4

B/F/S Inspiration Image Gallery 1/4

Injectable-SVPs 2-5ml small volume parenterals

Injectable-SVPs 10-100ml small vol. parenterals

Injectable-Large volume parenterals

Injectable-SVP using insertion technology

B/F/S Inspiration Image Gallery 2/4

Injectable-LVP design options

Eye Care-Spike top containers in 5-20ml

Eye Care-Tip/cap multi dose vialsCare-Tip/cap

Eye Care-eyewash, contact lens solution bottles

B/F/S Inspiration Image Gallery 3/4

Eye Care-Unit dose for one time ophthalmic use

Biologicals vial pack

Respiratory Therapy-nebulizer and PP bottle, 500 ml

Respiratory Therapy-R/T unit dose 0.5 - 3ml

B/F/S Inspiration Image Gallery 4/4

Irrigation/wound cleaner bottles

Beverage electrolyte, sport drinks-High Res

Drivers Affecting Innovation and the

Resin Choices for B/F/S Processing

Examples of Container Cost Savings

Topics of concern CONTINUED

Blow/Fill/Seal Insertion Technology Increases

Weiler Engineering, Inc.

About the Author

1395 Gateway Drive, Elgin, IL 60124

Chuck Reed has

Weiler Engineering, Inc. is a world leader in providing

He is a 15+ year member of both PDA and ISPE, is

Advances in Aseptic Blow/Fill/Seal

The latest improvements in aseptic Blow/Fill/Seal technology are providing

flexibility in packaging design, low operating cost and

CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of

CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of

meets Class 100 (ISO 5) microbiological standards during

more than 99 percent. The KleenKut mechanism assures that

The FDAs 2004 Guidance for Industry Sterile Drug Products

Any intervention or stoppage during an aseptic process can

CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of

endotoxin. The challenge was performed with an advanced

CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of

such as Penicillin sp. and Aspergillus sp., as well as bacteria

CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of

CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of

and end-user requirements. These application challenges

The company uses the latest technological advances in

Aseptic Blow/Fill/Seal: A Sustainable Process

Aseptic Blow/Fill/Seal systems for packaging pharmaceutical liquids incorporate

for our survival and well-being depends, either directly or

CONTINUED Aseptic Blow/Fill/Seal: A Sustainable Process