WeilerEbook V5

E-BOOK
BLOW/FILL/SEAL:
AN ADVANCED ASEPTIC
PACKAGING TECHNOLOGY
SPONSORED BY
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BLOW-FILL-SEAL: AN ADVANCED
ASEPTIC PACKAGING TECHNOLOGY
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
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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
stertility assurance and patient safety. CLICK
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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). Provide Critical
• Non-sterile medical devices (douche and enema) Advantages for
• Sterile devices, diagnostics and pharmaceuticals Sustainable Initiatives
(respiratory diluents, RT drugs, ophthalmics) for Processing and
• In 1993 the first biologic was approved for packaging with B/F/S technology Packaging
• General trend towards the manufacturing of injectable drugs Pharma Liquids.
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Current Regulatory Viewpoint
• 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
1 When the parison
2 The mold is
3 The fill assembly
4 The mold opens and
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is extruded into a tubular reaches the proper conveyed into position retracts and separate formed, filled and sealed
shape called a parison. length, the mold indexes, under the blowing/filling sealing molds close to container is conveyed out
pinching the bottom of the nozzle assembly. The form the top, hemetically of the machine.
parison closed. The top of nozzle is lowered into the sealing the container.
the parison is held open parison, forming a seal
while the parison is cut. with the neck of the mold.
The container is formed
by vacuum or assisted
by blowing with sterile
Process Advantages filtered air, expanding the
parison against walls of
the integrally cooled mold
Why Do Companies Typically cavity. While in position,
Use B/F/S Systems? the sterile air is vented
• Flexibility in Packaging Design from and sterile liquid
• Low Operating Cost product is metered into
the container through the
• High Degree of Sterility Assurance fill nozzle.
• Small Space Requirement
• Limited Component Inventory
• Limited Number of Operators Required
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What kind of containers may be produced?

• Vials with inserted tip / cap • Respiratory care
• Vials with a twist-off and re-closeable • Electrolyte and Sport Drinks
• Multi-dose use bottles • Rubber stopper insertion
• Eye wash and contact lens solution • Euro Cap
• Unit Dose Injectable • Spike Top
B/F/S INSPIRATION
IMAGE GALLERY
CLICK THROUGH THE NEXT 4

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 Eye Care-eyewash, contact lens solution bottles
multi dose vials 5-20ml
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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
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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% A comparison of
traditional packaging
3. Desire for more user friendly drug delivery system 23.7% v. Blow/Fill/Seal
technology
4. Improved stability of the product in plastic 13.2%
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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.
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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 Maximize Uptime,
- Polypropylenes. Excellent barrier properties and good clarity Minimize Changeover
and high temperature terminal sterilization time and increase
overall equipment
effectiveness (OEE)
Examples of Container Cost Savings
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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.
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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.
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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 SOP’s 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. CLICK
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Weiler Engineering, Inc. About the Author
1395 Gateway Drive, Elgin, IL 60124 Chuck Reed has

PHONE: 847/697-4900 - FAX: 847/697-4915 extensive experience
Website: www.asep-tech.com in specialized
equipment design
Weiler Engineering, Inc. is a world leader in providing and manufacture,
sterile, aseptic liquid packaging equipment for process technology
pharmaceutical and healthcare applications. Weiler is and pilot plant design
committed to the highest standards of excellence and and construction.
to further expanding products and systems to enhance
patient care. He is a 15+ year member of both PDA and ISPE, is
past Chairman of the ISPE Packaging Community
Weiler’s proprietary ASEP-TECH® Blow/Fill/Seal packaging of Practice and continues to serve on this COP
machines produce shatterproof, durable, sterile aseptically steering committee. He is an author for the ISPE
packaged products in one uninterrupted operation on a Packaging, Labeling and Warehousing (PACLAW)
single, compact machine frame without human intervention, Baseline Guide. He is currently Chairman of the
ensuring that parenterals, injectables, ophthalmic solutions, PDA Blow/Fill/Seal Interest Group, member of the
and respiratory drugs reach the marketplace in the most PDA Blow/Fill/Seal Technical Report Task Force
sterile, cost-effective manner possible—every time. and a chapter author in the PDA 2-volume Aseptic
Processing text. Mr. Reed holds a Bachelor of
The ASEP-TECH® System from Weiler is the culmination Science in Chemical Engineering from Clarkson
of more than 50 years of innovation in machine design University and a Master of Science in Management
and sterile process development, resulting in the most from National Louis University.
advanced aseptic liquid packaging process available
today through the application of Blow/Fill/Seal Email solutions@weilerengineering.com
technology. Our Vision - Building quality equipment to contact Chuck.
profitably, Fostering innovation and Satisfying customers.
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ASEPTIC PACKAGING TECHNOLOGY APPENDIX
BLOW/FILL/SEAL:
AN ADVANCED ASEPTIC
PACKAGING TECHNOLOGY
APPENDIX
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Advances in Aseptic Blow/Fill/Seal BACK TO EBOOK
Processing of Pharmaceutical Liquids Improve

Product Integrity and Patient Safety
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 process- flexibility in packaging design, low operating cost and
ing of pharmaceutical liquids have experienced rapid a high degree of sterility assurance. Due to its design
and growing acceptance by the pharmaceutical indus- and functionality, B/F/S processing inherently produces
try over the past 20 years. This has been accelerated very low levels of particulate matter, and much of the
by enhancements made to aseptic B/F/S processes potential for microbial contamination in its critical areas
based on pharmaceutical industry input and to ac- is mitigated by the absence of human intervention in
commodate the requirements of regulatory agencies. these areas.
These enhancements were designed to improve prod-
uct integrity and help ensure patient safety. As a result, Microbial contamination is a serious issue for compa-
the United States Food and Drug Administration and nies manufacturing liquid pharmaceutical formulations.
the United States Pharmacopoeia now characterize Such liquids are ideal growth areas for bacteria like Sal-
modern B/F/S technology as an “advanced aseptic monella, Escherichia coli and Staphylococcus microbes
process”, indicating its use as a preferred technology that have been found in various liquid drug products.
over other aseptic systems and a better solution for the A supposedly sterile, but con-
sterile, aseptic processing of pharmaceutical liquids. taminated product may result
Aseptic B/F/S systems offer a unique combination of in deterioration of the drug
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CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of BACK TO EBOOK

Pharmaceutical Liquids Improve Product Integrity and Patient Safety
and loss of potency, and with parenterals can cause py- classified environment. Various in-process control param-
rogenic reactions after administration to patients. The eters, such as container weight, fill weight, wall thickness
majority of liquid drug product contamination over the and visual defects provide information that is monitored
past several decades has come about from products and facilitates ongoing process control. Its containers are
produced in conventional (non-B/F/S) aseptic process- formed from a thermoplastic granulate, filled with a liquid
pharmaceutical product and then sealed in a continuous,
ing facilities. In conventional aseptic processing, the
integrated and totally automated sequence – the critical
drug product, container and closure are subjected to fill-zone area is shrouded under a continuous flow of posi-
sterilization processes separately, and then brought tive-pressure sterile filtered air. The B/F/S cycle is complet-
together. There is no further processing to sterilize the ed within seconds. This reduces the amount of components
product after it is in its final container, therefore it is contacting the product, and limits operator intervention
critical that containers be filled and sealed in an ex- particularly with system changeovers and cleaning.
tremely high-quality environment.
Recent B/F/S equipment designs employ the use of spe-
Automation Upgrades Improve Sterility cialized measures to reduce particle levels and minimize
Assurance in the B/F/S “Critical Zone” potential microbial contamination of the exposed product
Aseptic B/F/S technology integrates blow molding, sterile in the plastic extrusion and cutting zone. Non-viable par-
filling and hermetic sealing in one continuous operation to ticles generated during the plastic extrusion, cutting, and
produce aseptically manufactured pharmaceutical liquid sealing processes are thoroughly controlled.
products. Unique to aseptic B/F/S systems compared to
traditional aseptic processing, is its capability for rapid con- Provisions for carefully controlled airflow protect the prod-
tainer closure and minimized aseptic interventions. uct by forcing created particles outward while preventing
any inflow from the adjacent environment. This B/F/S zone
The most advanced aseptic B/F/S systems are quite auto- of protection is continually supplied with HEPA-filtered air,
mated, designed to require minimum human access and by an air shower device (shroud).
reduce risk to the product’s integrity, while operating in a Air in the critical filling zone
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meets Class 100 (ISO 5) microbiological standards during more than 99 percent. The KleenKut mechanism assures that
operations. Sterile air management within this critical zone non-viable particles 0.3μm to 10μm in size are significantly
is typically verified through environmental monitoring for reduced in quantity compared with the volume of particles
the presence of non-viable particulates. produced during the use of a hot-knife cut-off mechanism.
Non-viable particles in the B/F/S process primarily origi- The FDA’s 2004 Guidance for Industry Sterile Drug Products
nate from the electrically heated cut-off knife contacting Produced by Aseptic Processing states that the design of
the molten parison (an extruded tube of hot plastic resin equipment used in aseptic processing should limit the
through which sterile support air passes during the extru- number and complexity of aseptic interventions by person-
sion sequence). Past attempts to manage non-viable partic- nel. Both personnel and material flow should be optimized
ulate generation in this zone of protection were targeted to to prevent unnecessary activities that could increase the
the removal of particles after they were produced. Included potential for introducing contaminants to exposed product,
in recent improvements was the development of parison container-closures or the surrounding environment. It states
shrouding, which produces a controlled air environment by further, that airborne contamination is directly related to the
employing an exhaust blower system with differential pres- number of people working in a cleanroom and the level of
sure controls in conjunction with containment ductwork in congregation by personnel in areas where critical aseptic ma-
the parison cut-off area, to siphon away smoke created by nipulations are performed.
the hot knife – a heated high-resistance wire.
Any intervention or stoppage during an aseptic process can
A new technology was introduced to eliminate the gener- increase the risk of contamination. The design of equipment
ation of the parison-cutting smoke altogether – the Kleen- used in aseptic processing should limit the number and com-
Kut® parison cut-off mechanism. The device is an automat- plexity of aseptic interventions by personnel.
ed 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
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Reduced Airborne Microbial Bioburden in Recent endotoxin. The challenge was performed with an advanced
Challenge Study of Advanced B/F/S System aseptic B/F/S system supplied by Weiler Engineering, Inc.
Challenge studies on aseptic B/F/S systems have been
performed over the past 20 years which have correlated the Sterility of B/F/S polymeric containers, materials and pro-
microbial bioburden of environmental air in a B/F/S fill-room cesses is validated by verifying that time and temperature
to the potential contamination rate of product which is filled conditions of the extrusion, filling and sealing processes are
on machines in those rooms. These studies have led to an effective against endotoxins and spores. This report states
increased understanding of the capabilities of aseptic B/F/S “The extruder challenge studies, employing spore polymer
technology in the production of sterile products. and endotoxin polymer, have provided definite evidence
for polymer extrusion having the capability to produce vials
B/F/S system manufacturers should base their product de- ‘free’ of viable microorganisms and possessing acceptable
velopment on such studies, including materials testing spe- endotoxin levels.”
cifically for microbial challenges, which have been support-
ed with scientific evidence that the researched machines The challenge study demonstrates a uniform capability of
function within the standards of accredited agencies. achieving high sterility assurance levels (10-6 SAL) through-
out the entire process. Even higher sterility assurance lev-
One of the more recent B/F/S challenge studies was con- els, approaching 10-8 SAL, have been achieved using high
ducted in 2004 by Cardinal Health, Inc. and Air Dispersions, levels of airborne microbiological challenge particles.
Ltd. entitled “Evaluation of Blow/Fill/Seal Extrusion through
processing of Polymer Contaminated with Bacterial Spores A critical aspect of B/F/S technology is its pyrogen-free
and Endotoxin”, a study that was carried out to further the molding of containers and ampoules. Extensive experi-
understanding of the extrusion process and its impact upon ments in this challenge study confirm the efficacy of the
the quality of Blow/Fill/Seal product. Controlled challeng- B/F/S extrusion process, having been performed using
es were conducted to the extrusion system, comprising high levels of spores and endotoxin-contaminated polymer
low-density polyethylene granulate contaminated with Ba- granules. Results demonstrated
cillus atrophaeus endospores and Escherichia coli bacterial fractional spore contamination
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levels of less than 1x10-6, and a three-log reduction in such as Penicillin sp. and Aspergillus sp., as well as bacteria
endotoxins with the probability of a non-sterile unit (PNSU) like Bacillus sp. Paper, also used in the shipping of glass,
approaching one in one million. can also contain mold spores. The rubber closures used on
the glass containers can have mold contamination.
Expanded Options for B/F/S Packaging and
Delivery Solutions of Pharmaceutical Liquids Aseptic B/F/S-produced small-volume parenterals, such as
B/F/S processing resins, polyethylene and polypropylene, those used for local anesthetics, vitamins, vaccines and oth-
used to produce aseptic containers for injectables, ophthal- er standard injectable products, can be manufactured with
mics, biologicals and vaccines are generally considered in- a twist-off-opening feature. They can also be combined
ert by the FDA, and many of the blow molding resins used with a controlled-diameter form in the top to accommodate
in B/F/S processing have received international acceptance needle-less spikes. Luer locks or luer-slip fits can also be
as suitable for pharmaceutical liquids applications. These provided for making leak-free connections. For 2 to 5 mL
inert materials do not contain additives, have low water va- small volume parenterals, syringes can be connected direct-
por permeability, and are easy and safe to handle in critical ly to the ampoules without a needle, creating an inherently
care environments such as hospitals. safer packaging solution.
Of particular interest within the pharmaceutical industry, is B/F/S-produced, one piece, plungerless sterile syringes
the use of plastic material for the B/F/S production of small (designed for pre-filling) for use in flushing hospital equip-
volume parenterals. Plastic ampoules offer significant ad- ment such as catheters, are available for replacing tradi-
vantages over rubber-stopper glass vials. There is the safety tional two-piece plunger-type syringes. The B/F/S syringe
issue – glass vials are subject to breakage, both in transit provides an offset chamber for trapping air, and preventing
and while being administered. Handling glass containers it from being dispensed during drug delivery.
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 trans-
ported in cardboard boxes that can contain mold spores,
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The increased focus on biologics, proteins and other com- multientry rubber stopper or a controlled diameter injec-
plex solutions has brought B/F/S technology to the fore- tion-molded insert, useful where multiple administration
front. These pharmaceutical products often cannot with- of a drug is required. Viscous products, with apparent
stand exposure to high temperatures for extended periods viscosities of less than 15,000 centipoise, and suspension
of time without degradation of their active components, products can be handled by B/F/S machines with specially
making conventional terminal sterilization an unaccept- designed product fill systems. These types of products use
able method to produce a “sterile” product. Temperature innovative liquid-handling systems to maintain multiple-
sensitive biological and protein-based products can be component products in a homogeneous solution during the
processed in advanced B/F/S machines, providing a level filling process. Basically, if the solution will flow and if it can
of enhanced sterility assurance. Bulk sterilization, steriliza- tolerate a minimum residence time, it can be packaged in
tion by gamma or e-beam irradiation, or filter sterilization an advanced aseptic B/F/S machine.
followed by direct packaging utilizing the B/F/S process
are used successfully for these types of products. B/F/S is The latest advanced models of aseptic B/F/S systems are
demonstrating less than a one-degree C temperature rise in capable of manufacturing containers ranging in size from
a liquid pharmaceutical which is packaged in a 5 mL poly- 0.2 mL to 1,000 mL at production rates of up to 15,000
ethylene vial. units per hour. Pharmaceutical companies that use such
technological advances in aseptic B/F/S equipment design
Advanced B/F/S technology can also include the applica- and systems will realize the highest level of quality in the
tion of insertion technology to permit the incorporation of a production of their sterile liquid products. The ability to
sterile tip and cap insert into the Blow/Fill/Seal package to provide these B/F/S systems, which must meet corporate,
produce a calibrated drop. This process enables increased scientific, regulatory and end-user requirements, can be a
efficiency and sterility control in the processing of expen- quite demanding. These application challenges are being
sive drug formations for treatment of glaucoma and other met, however, by continuously evolving and improving
eye diseases. Other types of sterile inserts can be incorpo- B/F/S system and container designs, driven by the need for
rated into the basic B/F/S-produced container as well. Top enhanced product integrity and
geometrics for both bottles and ampoules can include a patient safety.
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About Weiler Engineering: and end-user requirements. These application challenges

Weiler Engineering is a worldwide provider of aseptic Blow/ are met through the offering of several machine models
Fill/Seal custom packaging machinery for pharmaceutical designed to manufacture containers ranging in size from 0.1
and healthcare applications. Based in Elgin, Illinois, and mL to 1,000 mL at production rates of up to 15,000 units per
founded in 1959, Weiler’s proprietary Blow/Fill/Seal system hour, depending on container configuration.
is the culmination of 40 years of innovation in machine de-
sign and sterile process development, producing a highly To reach Weiler Engineering, please contact Chuck Reed;
advanced aseptic liquid packaging system. Its ASEP- 1395 Gateway Drive, Elgin, Illinois 60124; Phone 847-697-
TECH® Blow/Fill/Seal technology integrates blow molding, 4900; email solutions@weilerengineering.com;
sterile filling and hermetic sealing in one continuous opera- www.weilerengineering.com
tion 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 equip-
ment must meet demanding corporate, scientific, regulatory
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Aseptic Blow/Fill/Seal: A Sustainable Process BACK TO EBOOK
for Packaging Pharmaceutical Liquids

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 internation- for our survival and well-being depends, either directly or
al markets. The pharmaceutical industry is no exception, indirectly, on our natural environment. Sustainability cre-
considering its environmentally taxing processes involv- ates and maintains the conditions under which humans and
ing solvents, reagents, water and other agents. Along nature can exist in productive harmony, that permit fulfilling
with sterility assurance, process validation and regulatory the social, economic and other requirements of present and
compliance, sustainability is becoming a more high-profile future generations.”
component in pharmaceutical processing, and is consid-
ered a critical factor in the design of healthcare equip- The major emphasis with sustainable procedures in phar-
ment, products and packaging. maceutical manufacturing is directed to the reduction of
environmental impact, by decreasing consumption of raw
The concept of sustainability has been a topic of interest materials and energy usage in manufacturing and pack-
for many years, and has been more formally discussed and aging processes, and by increasing the utilization of more
considered since the late 1980’s. Current international recycled materials.
focus has led to the development of regulatory guidance in
many of the world’s markets. There are many processes in pharmaceutical manufactur-
ing that can be addressed to improve sustainability, and at
The United States Environmental Protection Agency has the same time reduce operating costs. One of the most
posted the following definition of sustainability on its web- critically important objectives in
site www.epa.gov/sustainability/basicinfo.htm: “Sustainabil- achieving sustainability is reduc-
ity is based on a simple principle: Everything that we need ing process energy consumption.
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CONTINUED Aseptic Blow/Fill/Seal: A Sustainable Process BACK TO EBOOK

Implementing energy-efficient practices and technologies

should be a senior priority at the component, process and B/F/S is a self-contained process, where the raw materials
system levels. are virtually completely recyclable. The consolidation of
process steps through the use of B/F/S results in a signifi-
Energy monitoring systems and process control systems cant reduction in the carbon footprint for the entire liquid
are key tools that play an important role in energy manage- filling and packaging production process. The products
ment to reduce energy use. Such systems include meter- produced by aseptic B/F/S present a strong platform for
ing, monitoring, and system controls such as integrated sustainability from a variety of perspectives.
programmable logic controllers (PLCs). These minimize
the time required to perform complex tasks and increase Assessing Sustainability in Pharmaceutical Manufacturing
efficiency in process operations. Such automated process Pharmaceutical manufacturers possess a wide degree of
technologies that reduce energy consumption can also latitude in selecting and implementing systems for achiev-
improve product quality and consistency, and increase pro- ing environmental sustainability and energy efficiency. But
duction throughput. foremost is the necessity to have a structured methodology
that clearly delineates overall sustainability initiatives and
Embracing process sustainability and energy efficien- process improvements.
cy in the pharmaceutical industry is the aseptic Blow/
Fill/Seal (B/F/S) system for packaging pharmaceutical Two basic types of structured programs are available to
liquids, which has made significant strides in achieving companies that manufacture pharmaceutical products: a)
sustainability objectives. programs that address multiple aspects of sustainability,
Aseptic B/F/S technology integrates the three-step process such as LEED (Leadership in Energy and Environmental De-
of blow molding, sterile filling and hermetic sealing in one sign), which provides a step-by-step process to achieve cer-
continuous, highly-automated operation. Unique to aseptic tification and recognition of having reached specific levels
B/F/S systems compared to traditional aseptic processing of compliance; and, b) programs that provide assessment
is their capability for rapid container closure and minimized and planning tools for reducing
aseptic interventions. energy consumption and plant
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process costs. Both types of programs use a set of guide- ed sustainability program would be needed to accurately
lines for evaluating the environmental impact involved assess environmental impact.
when manufacturing, packaging and distributing a product.
Similar to LEED is Green Globes, operated by the Green
LEED is a certification program developed by the U.S. Building Initiative in the United States. Green Globes is a
Green Building Council (USGBC) that can be applied to any building environmental design and management tool used
building type and any building life cycle phase. It provides throughout the United States and Canada. It encompasses
a framework for identifying and implementing practical and both sustainability and energy management criteria, such
measurable green building design, construction, operations as integration of energy efficient systems, renewable en-
and maintenance solutions. ergy, cogeneration and on-site wastewater treatment sys-
tems, in additional to sustainable environmental practices
LEED promotes a whole-building approach to sustainabil- such as sustainable site development and indoor air quality.
ity by recognizing performance in key areas, such as sus-
tainable sites, water efficiency, energy, materials, indoor Green Globes delivers an online assessment protocol,
environmental quality, location and building design. The rating system and guidance for green building design,
program’s internationally recognized green building cer- operation and management for light industrial applications
tification system provides third-party verification that a like pharmaceutical manufacturing. But the program does
building was designed and built using strategies aimed at not govern industrial process – which omits the significant
improving performance across these metrics. energy savings that can be achieved when taking these
processes into account.
Although LEED certification does cover the actual phys-
ical facility and its habitable spaces, it does not provide The Building Research Establishment’s Environmental As-
benchmarks for manufacturing and packaging processes sessment Method (BREEAM) is a leading European envi-
within the plant. For pharmaceutical manufacturers, whose ronmental program for building practices in sustainable
plant operations represent a significant energy draw which design. The program can assess
sizably impacts their sustainability, a more process-orient- light industrial operations like
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pharmaceutical plants, such as manufacturing, assembly benefit is that it allows industrial companies to measure the
and packaging facilities both at the design stage and after energy use of their facility, and to benchmark it with other,
construction. Factors considered are energy management, similar facilities. Companies input key plant operating data
wastewater, land use, pollution, building materials, and into an energy performance indicator to receive an effi-
other sustainability factors. Credits are awarded in each of ciency score. It is a critical management tool for evaluating
the above areas according to performance. A set of envi- how efficiently a plant is using energy compared to other
ronmental weightings then enables the credits to be added companies in their industry.
together to produce a single overall score.
Also supporting energy efficiency in pharmaceutical pro-
But like LEED and Green Globes, process assessment is not cesses is the DOE’s Industrial Technologies Program (ITP),
covered in this program, which means it is an incomplete run by the Office of Energy Efficiency and Renewable
assessment system for the sustainability requirements of Energy. This program addresses process functions in man-
pharmaceutical manufacturers. ufacturing plants that utilize steam, compressed air, process
heat, electric, and other systems that could potentially be
A program that does address process in pharmaceutical a source of wasted energy. It focuses on the reduction of
plants is Energy Star, sponsored by the U.S. Department of energy usage by integrating new technologies in industrial
Energy (DOE), and administered through the Environmental controls, automation and robotics, and provides concrete
Protection Agency. Its program provides tools and resourc- guidelines to achieve energy sustainability.
es to help improve the energy efficiency of manufacturing
and industrial facilities, including plant manufacturing and The ITP regularly conducts and makes available analytic
packaging processes. studies to identify energy-reduction opportunities with-
in industrial processes, making these results available to
Energy Star supplies an energy guide specifically for the participant manufacturers. Application of the ITP program
pharmaceutical industry, which helps manufacturers evalu- has resulted in significant energy savings, waste reduction,
ate potential energy improvement options, and develop ac- increased productivity, lowered
tion plans and checklists for the energy program. A major emissions and improved product
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SPONSORED BY

quality for U.S. industrial manufacturers. material extraction through materials processing, manufac-
ture, distribution, use, repair and maintenance, and dispos-
Choosing the right program is critical to how quickly a al or recycling. LCA can be used to find the most ecolog-
pharmaceutical manufacturer’s energy efficiency and sus- ical way to improve product manufacturing, and can be a
tainability goals can be achieved. A company’s best strat- useful decision-making tool for new products and process
egy may be to utilize more than one of these programs. development. It can also be used as a guide for the opti-
A plant may decide to run with Energy Star or ITP for its mization of energy and raw material consumption.
process energy improvements, while simultaneously going
with LEED or Green Globes for its other sustainability ini- Cradle-to-grave life cycle analysis, through mathematical
tiatives. Or, a manufacturer may choose to integrate state modeling, makes it possible to determine and manipulate
energy efficiency programs with LEED, Green Globes or ITP key metrics to provide a weighted average on total sustain-
to capitalize on state energy credits or low interest loans ability. Values for energy and resource consumption, the
and grants that the states may offer for energy-efficient extraction and processing of the raw materials, the pollu-
solutions or equipment. tion produced, recyclability and the effects of associated
transportation on the environment are applied in a numeri-
Life Cycle Analysis and B/F/S cal equation.
The environmental performance of products and processes The weighted average then gives a clear evaluation of a
in all industrial sectors, including pharmaceutical processing, sustainable solution for the product and manufacturing/
has become a key issue. To better determine how sustain- packaging process being examined.
able products and processes really are, life cycle analysis The LCA process is a systematic, phased approach and
(LCA) has emerged as a recognized instrument to assess the consists of four components: 1) establishing the context
ecological burdens and impacts connected with them. and parameters of the analysis; 2) an inventory, consisting
of an identification and quantification of energy, water and
A life cycle analysis is unique as a technique because it as- materials usage and environmental releases; 3) an impact
sesses environmental impacts associated with all stages of assessment of these inventory
a product’s life from cradle to grave. This includes from raw factors, and the potential human
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and ecological effects; and 4) the different environmental across its influence on air, water and land. The packaging
impacts are weighted relative to each other, then summed process may use a film that is difficult or impossible to recy-
to get a single number representing the total environmen- cle. Therefore, the unselected process may now be viewed
tal impact. as producing less cradle-to-grave environmental harm or
impact than the initial preferred technology.
An LCA allows a decision maker to study an entire product
system and its processes, thereby avoiding the sub-opti- From a life cycle analysis perspective, aseptic Blow/Fill/Seal
mization that could result if only a single process were the machines that provide packaging of pharmaceutical liquids
focus of the study. present much more streamlined and sustainable systems
for production of sterile products, compared to traditional
In a comparison of different liquid pharmaceutical contain- aseptic processing in a number of critical aspects:
ers, for example, to determine which container had the
lowest releases to the environment and least affected the Energy Management – The most advanced aseptic B/F/S
supply of natural resources, an LCA would quantify the raw systems are quite automated, compared to traditional
materials used and the environmental loadings (including aseptic processing. These B/F/S machines are designed
energy consumption) from the manufacturing and packag- to require minimum human access while operating in
ing processes used to produce each container. Also viewed Class-100 environments.
would be comparative ecological impacts from distribution,
consumption and disposal or reuse of each container. Various in-process control parameters utilizing the latest
generation of fully system-integrated PLCs, control and
When selecting between two packaging processes, for ex- monitor container weight, fill weight, wall thickness, iso-
ample, it may appear that one is better for the environment lation of visual defects and other factors, facilitating opti-
because it generates less chemical emissions at the point of mized system function.
packaging. However, after performing an LCA, it could be
determined that the preferred process actually creates larg- These B/F/S machines allow very
er cradle-to-grave environmental impacts when measured efficient processing speed and
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SPONSORED BY

short machine cycle times. Aside from the obvious im- and used for other applications. The entire production and
provement in throughput volume, they provide more effi- recycle processes can be maintained on-site with minimal
cient energy usage. need for off-site disposal of waste material.
According to the DOE’s Energy Star program, implementa- Reduced Manual Interventions – Waste reduction should
tion of monitoring and control systems, such as PLCs and be viewed as an important objective in a sustainability
servo-drives, present well-documented opportunities for program. In aseptic packaging of pharmaceutical liquids,
energy savings. waste can manifest itself in compromised quality, labor-in-
tensive processes and reduced efficiency.
Recyclable Plastic Containers – Aseptic B/F/S systems in-
corporate the use of recyclable plastic resins, as differentiat- Traditional aseptic procedures for packaging pharmaceu-
ed from glass containers used in traditional aseptic process- tical liquids involves multiple steps in the handling and
ing. Low-density polyethylene, high-density polyethylene manipulation of the material, containers and sterilization
and polypropylene, used to produce aseptic containers for filling processes with human intervention, and therefore
injectables, ophthalmics, biologicals and vaccines are gen- have a higher potential for contamination during process-
erally considered inert by the FDA. These inert materials ing. Additional processing steps for conventional aseptic
do not contain additives, have low water vapor permeabil- processing include receiving, inspection and warehousing
ity, and are easy and safe to handle in critical care environ- of incoming containers, washing and sterilizing of contain-
ments such as hospitals. ers, separate processing steps and equipment for filling
and sealing, and end processing handling such as labeling.
These resins used in B/F/S processes are recyclable. Reg-
ulatory requirements permit reuse of the resin up to three The FDA’s 2004 Guidance for Industry Sterile Drug Products
times before it must be discarded. As much as 50 percent Produced by Aseptic Processing states that the design of
of the resin used in the B/F/S process can be reground and equipment used in aseptic processing should limit the num-
directly used again within the process when mixed with vir- ber and complexity of aseptic
gin material. The remainder of the waste can be captured interventions by personnel.
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SPONSORED BY

Both personnel and material flow should be optimized dropper units for eye drop containers used to deliver a cal-
to prevent unnecessary activities that could increase the ibrated drop, are attached to the container after the blow-
potential for introducing contaminants to exposed product, ing and filling process. These improvements streamline the
container-closures or the surrounding environment. packaging process.
The latest generation of Blow/Fill/Seal machines, as ex- Changeover Flexibility – When aseptic throughput is in-
emplified in the ASEP-TECH® B/F/S system from Weiler terrupted, or not running because of downtime, the entire
Engineering, are highly automated, thereby severely reduc- process line is affected, which represents a significant pro-
ing manual interventions. The forming, filling and sealing duction loss to the manufacturer. Many B/F/S machines are
steps are achieved in one unit operation – the cycle being configured to produce more than one bottle shape or for-
completed within seconds. Such automation eliminates mat. This makes it easy to change over from one container
unneeded manpower and reduces the risk to lessened size to another. A Blow/Fill/Seal machine might produce a
product integrity. 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
Elimination of Secondary Packaging – B/F/S produced vi- other with relative ease of machine set-up.
als and bottles, by virtue of their opening features and sim-
plified designs, such as twist-off tops, eliminate the need B/F/S systems approach 99 percent uptime efficiency, sig-
for secondary packaging. Labeling is not needed, since nificantly higher than traditional aseptic processing, which
the molds can be engraved with product information. This is plagued with slow-downs and process interruptions in
avoids an additional process step, and eliminates material part because of required manual interventions.
usage and the potential for additional waste generation.
Embracing Sustainability
Integrated Packaging of Inserts – B/F/S allows pre-mold- The Blow/Fill/Seal system improves product integrity and
ed, pre-sterilized components, called inserts, to be inte- better ensures patient safety over traditional aseptic pro-
grated into the basic container. These inserts, including cessing procedures. As a result,
items such as rubber and silicone stoppers, and tip-and-cap the United States Food and Drug
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SPONSORED BY

Administration and the United States Pharmacopoeia now and founded in 1959, Weiler’s proprietary Blow/Fill/Seal
characterize modern B/F/S technology as an “advanced system is the culmination of 40 years of innovation in ma-
aseptic process”, indicating its use as a preferred technolo- chine design and sterile process development, producing a
gy over other aseptic systems, and a better solution for the highly advanced aseptic liquid packaging system. Its ASEP-
sterile, aseptic processing of pharmaceutical liquids. TECH® Blow/Fill/Seal technology integrates blow molding,
sterile filling and hermetic sealing in one continuous opera-
Waste reduction, resource and energy management, im- tion to produce aseptically manufactured products.
proved process controls and throughput efficiency are
key factors that have influenced the acceptance of aseptic The company uses the latest technological advances in
Blow/Fill/Seal. These are critical functions for achieving equipment design and systems to ensure the highest level of
sustainable practices in the packaging of aseptic pharma- quality in the production of sterile liquid products. Its equip-
ceutical liquids. They save energy, increase productivity, ment must meet demanding corporate, scientific, regulatory
and reduce environmental impacts. and end-user requirements. These application challenges
are met through the offering of several machine models de-
Advanced aseptic Blow/Fill/Seal technology has emerged signed to manufacture containers ranging in size from 0.1 mL
as an innovation in green technology within the pharma- to 1,000 mL at production rates of up to 15,000 units per
ceutical packaging sector. As government agencies and hour, depending on container configuration.
pharmaceutical manufacturers steadily, but surely, embrace
the sustainability initiative, aseptic Blow/Fill/Seal technol- To reach Weiler Engineering, please contact Chuck Reed;
ogy will continue to occupy a prominent position in the 1395 Gateway Drive, Elgin, Illinois 60124; Phone 847-697-
evolution of “Green Processing”. 4900; email solutions@weilerengineering.com;
www.weilerengineering.com
About Weiler Engineering:
Weiler Engineering is a worldwide provider of aseptic Blow/
Fill/Seal custom packaging machinery for pharmaceuti-
cal and healthcare applications. Based in Elgin, Illinois,
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SPONSORED BY
Improving Process Quality of Pharmaceutical BACK TO EBOOK
Liquids – Aseptic Blow/Fill/Seal Technology

vs. Traditional Aseptic Processing
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 phar- human manipulation. The process provides flexibility
maceutical market more than 40 years ago, blow/fill/ in container design and system changeovers, high vol-
seal (B/F/S) aseptic processing has established itself ume product output, low operational costs and a high
as a highly efficient and safe system for the filling and assurance of product sterility. The inherent safety of
packaging of sterile pharmaceutical liquids and other the process – packaging sterile products under aseptic
healthcare products, such as creams and ointments. conditions without human intervention – has led the
B/F/S product usage has been widely established in FDA, and the United States Pharmacopoeia, to char-
the ophthalmic and respiratory therapy markets for acterize B/F/S technology as an “advanced aseptic
some time, and lately B/F/S technology has been gain- process”, indicating its use as a preferred technology.
ing increasing worldwide acceptance in the parenteral
drug marketplace, replacing traditional glass vial pro- New advances in drug delivery, the desire to improve
cessing in a growing number of applications. convenience in handling pharmaceutical products,
growing emphasis on combination products, the
B/F/S enables a container to be molded from plastic, increasing focus on pro-
aseptically filled and hermetically sealed in one con- tein-based drugs and other bi-
tinuous, integrated and automatic operation, without ologics, and tighter regulatory
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CONTINUED Improving Process Quality of Pharmaceutical Liquids – BACK TO EBOOK

Aseptic Blow/Fill/Seal Technology vs. Traditional Aseptic Processing
criteria on product safety, have focused more attention its final form. One system used is traditional process-
on B/F/S technology over traditional aseptic methods ing, followed by terminal sterilization, which involves
as a better solution for the sterile, aseptic processing initially filling and sealing product containers within a
of pharmaceutical liquids. cleanroom environment. The environment is set up to
minimize the microbial content of the product while it
Traditional Aseptic Processing and is being manufactured. Each component of the pro-
Sterility of Pharmaceutical Liquids cess – the product, container and closure – have a low
Microbial contamination is a serious issue for com- bioburden, but may or may not be sterile. The prod-
panies manufacturing liquid pharmaceutical formula- uct, in the final container, is subjected to a “terminal”
tions. Such liquids are ideal growth areas for bacteria sterilization process, such as heat or radiation. The
like Salmonella, E. coli and Staphylococcus, microbes most common method uses autoclaving with saturated
that have been found in various liquid drug products. steam under pressure.
A supposedly sterile, but contaminated product may
result in deterioration of the drug and loss of potency, Traditional aseptic processing allows a final sterile drug
pyrogenic reactions after administration to a patient product to be achieved by individually sterilizing the
– particularly in parenterals, infection of the patient containers, material and equipment in-process, result-
and colonization of microorganisms in the patient with ing in a unified sterilized product. In traditional aseptic
the risk of a secondary infection. Any microorganism, processing, the containers are either supplied cleaned
pathogen or nonpathogenic, found in a supposedly and sterilized to the filling line, or they are cleaned and
sterile pharmaceutical product is dangerous. sterilized within the aseptic filling line. Plastic contain-
ers are usually washed, dried, sterilized and cooled be-
Drug manufacturers have pursued various methods of fore filling. Glassware containers, which have been the
sterilizing packaging components, product ingredients dominating packaging materi-
and equipment in order to achieve a sterile product in al for terminally sterilized and
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traditionally sterilized pharmaceutical liquids, are usu- veying, filling and container sealing stages be careful-
ally sterilized in-line, exposed to hot air at 350 degrees ly controlled at each step of the process to maintain
C while being passed through a Class 100 tunnel. A sterility of the product. Traditional aseptic processing,
glass container temperature of 180 to 200 degrees C is involving filling open glass bottles or vials, requires
adequate for achieving sterility. that the manufacturer maintain aseptic conditions in
critical processing areas at all times. Unfortunately, the
Methods of sterilization used in aseptic processing in- majority of liquid drug product contamination over the
clude filtering the solution by dissolving it in a solvent, past several decades has come about from products
such as Water For Injection (WFI), where the solution is produced in traditional aseptic processing facilities.
passed through a sterilizing filter or membrane. Filter
sterilization is used where the component is soluble Personnel Intervention inTraditional
and likely to be adversely affected by heat. A variation Aseptic Critical Areas
of this method includes subjecting the filtered solution Traditional aseptic sterilization involves handling and
to aseptic crystallization and precipitation (Lyophiliza- manipulation of the material, containers, and steril-
tion) of the component as a sterile powder. Dry heat ization filling processes with human intervention, and
sterilization is another effective method for sterilizing therefore has a higher potential for contamination
components that are heat stable and insoluble. Irradi- during processing. The FDA’s 2004 Guidance for In-
ation can also be used to sterilize some components. dustry Sterile Drug Products Produced by Aseptic
Processing states that the design of equipment used in
Aseptic processing handles components, materials and aseptic processing should limit the number and com-
equipment in such a manner that foreign microbial and plexity of aseptic interventions by personnel. Both
endotoxin contaminents that exceed pre-determined personnel and material flow should be optimized to
acceptable levels, are not introduced to the product prevent unnecessary activities
stream. To this end, it is critical that all storage, con- that could increase the poten-
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SPONSORED BY

tial for introducing contaminants to exposed product, of established procedures for microbial decontamina-
container-closures or the surrounding environment. tion and potential introduction of other particulates
like dirt, oil and chemicals.
Ordinary walking by a person emits roughly 10,000 skin
particles per minute. Such particles can and do hold Mold is common flora found on floors, walls and ceil-
microbial contamination. A rip in a worker’s uniform, a ings of buildings. Contamination occurs due to the
momentary exposed wrist, a mask placed too low on retention of water in cracks, edges and joints that are
the nose or physical contact with an open fill port will susceptible because of inadequate sealing. Brooms,
increase microbial contamination within a critical area. mops and anything used for cleaning can become
contaminated and increase atmospheric contamination
According to the FDA’s guide, airborne contamination because of raised dust or splashing water. In tradition-
is directly related to the number of people working in a al aseptic processing, significant manual intervention
cleanroom and the level of congregation by personnel is required in critical areas to maintain compliance with
in areas where critical aseptic manipulations are per- established sterile mandates.
formed. Isolation of personnel from these critical areas
would eliminate the major source of contamination in Advanced Blow/Fill/Seal Aseptic Technology
traditional aseptic processing. In advanced aseptic B/F/S processing, containers are
formed from a thermoplastic granulate, filled with a
In traditional aseptic processing, changing or adjusting liquid pharmaceutical product and then sealed within a
filling nozzles and heads necessitates the shutdown of continuous, integrated and automatic operation with-
the filling operation and requires re-sterilization of the out human intervention.
entire equipment. This increases manual intervention
in this critical area. Cleaning and sterilization which is Bulk solution prepared under
carried out by personnel, opens the door to breaching low bioburden or sterile con-
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SPONSORED BY

ditions is delivered to the machine through a product deposit the stipulated volume of product into the
delivery system that has been previously sterilized container; (f) the filling needles are withdrawn, and the
using an automated steam-in-place process. upper part of the mold closes to form and seal the up-
per part of the B/F/S container; (g) the mold is opened
Modern B/F/S machines are fully automated, designed and the completed, filled containers are conveyed out
to require minimum human access and operate in a of the B/F/S machine to a remote station where excess
classified environment using the following steps: (a) plastic is removed and the finished product is then
granules of a polymer resin, conforming to a predeter- conveyed to final packaging.
mined set of specifications, such as polyethylene, poly-
propylene, co-polymers or other blow-moldable resins, Various in-process control parameters, such as contain-
are pneumatically conveyed from a non-classified area er weight, fill weight, wall thickness and visual defects
into the hopper of the B/F/S machine, from which the provide information that is monitored and facilitates
plastic is fed into a multi-zone rotating screw extruder ongoing process control.
which produces a sterile homogenous polymer melt
(160–250 degrees C); (b) then to a parison head which The forming, filling and sealing steps are achieved
produces hollow tubular forms of the hot resin (called in one unit operation – the cycle being completed
parisons). The parisons are prevented from collapsing within seconds. Automation of B/F/S process steps
by a stream of sterile filtered support air. Some high- eliminates manual intervention and reduces risk to the
speed B/F/S machines have up to sixteen parisons be- product. No production personnel are present in the
ing formed simultaneously; (c) container mold(s) close filling room during normal operation.
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 blow-
ing sterile air or creating a vacuum; (e) filling needles
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Microbial and Particulate Integrity spores and endotoxin-contaminated polymer granules.

in the Aseptic Blow/Fill/Seal System The typical B/F/S extruders have demonstrated spore
Sterility of B/F/S polymeric containers, materials and contamination rates of 0.000001 percent, and 0.00001
processes is validated by verifying that time and tem- percent for endotoxins.
perature conditions of the extrusion, filling and sealing
processes are effective against endotoxins and spores. Control of air quality is critical for sterile drug prod-
uct manufacture. B/F/S equipment design typically
Challenge studies have been conducted on the ste- employs the use of specialized measures to reduce
rility levels of advanced B/F/S technology, which microbial contamination and particle levels that can
demonstrate a uniform capability of achieving contaminate the exposed product. The B/F/S pro-
contamination rates not exceeding 0.001 percent cess inherently produces a very low level of particulate
throughout the entire process. Even higher sterility matter and much of potential B/F/S microbial contam-
assurance levels, approaching 0.000001 percent, have ination (viable) in the air is mitigated by the absence
been achieved using high levels of airborne microbio- of manual intervention in its critical areas. Non-viable
logical challenge particles. particles generated during the plastic extrusion, cut-
ting, and sealing processes are controlled. Provisions
Endotoxins are a potential pyrogenic contaminant, es- for carefully controlled airflow protect the product by
sentially dead bacterial cellular matter. They can lead forcing created particles outward while preventing any
to serious reactions in patients, particularly with those inflow from the adjacent environment. These “zones
receiving injections, ranging from fever to death. A of protection” can also incorporate designs that sepa-
critical aspect of B/F/S technology is its pyrogen-free rate them from the surrounding environment, provid-
molding of containers and ampoules. Extensive exper- ing additional product protection.
iments confirming the efficacy of the B/F/S extrusion
process have been performed using high levels of
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SPONSORED BY

The B/F/S critical processing zone is continually sup- quite demanding. It is not unusual for degradation
plied with HEPA-filtered air by an air shower device of the product to occur during processing or while in
(shroud). The B/F/S critical zone is the area where transit. The physical properties of liquids can be al-
the containers are exposed during filling. Air in the tered with inadequate packaging components. For
critical zone meets Class 100 (ISO 5) microbiological aseptic filling, the package must be produced, stored,
standards during operations. The critical zone is con- filled and sealed under conditions that preserve steril-
tinuously monitored to ensure a positive differential ity. Likewise, the appearance of particulates in sterile
pressure is maintained between the shroud and the solutions is equally undesirable.
adjacent cleanroom.
Glass, although a standard in the aseptic pharmaceuti-
Plastic vs. Glass Containers cal liquids industry, is not without its limitations. There
Injectables, ophthalmics, biologicals and vaccines are is the safety issue – glass vials are subject to breakage,
produced in a number of different types of containers, both in transit and while being administered. Handling
including bottles, vials and ampoules that are made glass containers always involves a certain amount of
from glass and plastic. Protecting the contents of risk of lacerations and glass splinters. Glass ampoules,
these aseptic liquid drugs through filling, packaging for example, generate a fine array of small glass parti-
and transportation, and allowing for safe and easy cles during opening.
administration are critical objectives in the aseptic
process. The industry is infused with a strong quality Manufacturers using glass containers are also subject-
control emphasis. Raw materials, and in-process and ed to design limitations when the designs become
finished products are continually checked for approval somewhat complex. With glass containers, as design
and rejection. complexity increases so does the cost. Once glass
containers are produced,
The packaging needs for pharmaceutical liquids are they need to be transported
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SPONSORED BY

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

rate sterile items (inserts) within the B/F/S container, More advanced B/F/S machines have been designed so
and in-mold coding and engraving, which provide they can handle these heat sensitive products.
further opportunities for innovative design over that
of glass products. Machine models are available that can produce con-
tainers ranging in size from 0.1mL to 1000mL at pro-
Flexibility with Changeovers Allows Shorter Runs, duction rates of 15,000 units per hour, depending on
Increased Uptime, Maximized Throughput container configuration.
Modern B/F/S system design is focused on simplicity
and flexibility. Many B/F/S machines are configured to B/F/S machine efficiency is very high. More advanced
produce more than one bottle shape or format. This B/F/S machines can approach 99 percent uptime ef-
makes it easy to change over from one container size ficiency, which is significantly higher than traditional
to another. A B/F/S machine might produce a family of aseptic processing which is plagued with slow-downs
2, 3 and 5ml, then switch to a family of 5, 10 and 15ml, in part because of manual interventions. To further
or to one of 10, 15 and 20ml, moving from one to the minimize potentials of system downtime, some manu-
other with relative ease of machine set-up. This is facturers are now segmenting their high-volume pro-
ideal for manufacturers performing contract packaging cess lines into more short-run lines, in the event that if
of aseptic liquid pharmaceutical solutions, because of one of the lines goes down for maintenance or repair,
their need for changeover flexibility. it will not stop the entire production throughput.
The growing usage of biologics is demanding packaging When aseptic throughput is interrupted, or not running
in different formats. They usually require smaller process because of downtime, the entire process line is affect-
runs and are typically heat sensitive. Many of these new ed, which represents a significant production loss to
biotechnological drugs do not withstand steam steril- the manufacturer.
ization or irradiation and so are best treated aseptically.
41
SPONSORED BY

An Aseptic Technology Destined to Prevail velopment, producing a highly advanced aseptic liq-
More rapid container closure processing, elimination uid packaging system. Its ASEP-TECH® blow/fill/seal
of aseptic critical-area personnel interventions, in- technology integrates blow molding, sterile filling and
creased system uptime over traditional processing, hermetic sealing in one continuous operation to pro-
pyrogen-free molding of containers and ampoules, duce aseptically manufactured products.
more flexibility with container design, and an increased
capability to capitalize on short runs – these are some The company uses the latest technological advanc-
of the benefits for manufacturers inherent in advanced es in equipment design and systems to ensure the
blow/fill/seal aseptic technology. And for consumers, highest level of quality in the production of sterile
increased safety and confidence in their drug products. liquid products. Its equipment must meet demanding
corporate, scientific, regulatory and end-user require-
These are advances that are significant, if not fully real- ments. These application challenges are met through
ized yet within the aseptic liquid pharmaceutical mar- the offering of several machine models designed to
ketplace. But it is apparent that advanced B/F/S asep- manufacture containers ranging in size from 0.1mL to
tic technology is destined to become a major player in 1000mL at production rates of up to 15,000 units per
this arena. hour, depending on container configuration.
About Weiler Engineering: To reach Weiler Engineering, please contact Chuck

Weiler Engineering is a worldwide provider of aseptic Reed; 1395 Gateway Drive, Elgin, Illinois 60123; Phone
blow/fill/seal custom packaging machinery for pharma- 847-697-4900; email solutions@weilerengineering.
ceutical and healthcare applications. Based in Elgin, com; www.weilerengineering.com
Illinois, and founded in 1959, Weiler’s proprietary
blow/fill/seal system is the culmination of 40 years of
innovation in machine design and sterile process de-
42
SPONSORED BY
Improving Uptime in Aseptic Processing of BACK TO EBOOK
Pharmaceutical Liquids with Blow/Fill/Seal

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 expe-

rienced exceptional growth with the development of new Overall Equipment Effectiveness
drugs and the marketing of these products, but pharmaceuti- An important tool that pharmaceutical manufacturers are
cal manufacturing processes have historically lagged behind using to increase uptime, and measure and improve line
in efficiency compared to those of other consumer product efficiency is Overall Equipment Effectiveness (OEE). OEE
industries. Within the past decade, however, responding to measurement is also frequently used as a key performance
changes in consumer purchasing such as the influence of the indicator (KPI) in conjunction with lean manufacturing ef-
Internet, stiffer guidelines from the Food and Drug Adminis- forts to provide an indicator of success.
tration and other regulatory agencies, and significantly in-
creased costs to bring new drugs to market, drug companies Overall Equipment Effectiveness (OEE) is a system of ana-
have had to take a closer look at their manufacturing process- lytics to determine how effectively a manufacturing opera-
es to make them more efficient, to stay competitive. tion is utilized. It identifies and quantifies the performance
of specific areas of a manufacturing line to bring about pro-
A key factor to reaching high levels of efficiency in phar- cess improvement. OEE is determined by factoring three
maceutical manufacturing is maintaining uptime, which has key metrics of machine and line operation: 1) availability; 2)
always been of critical importance to manufacturers in every performance; and 3) product quality.
industry. When throughput is interrupted, or not running
because of downtime or changeovers, the entire process Availability represents the per-
line is affected, which can present a significant production centage of scheduled time that
loss to the pharmaceutical manufacturer. the process is available to op-
43
SPONSORED BY
CONTINUED Improving Uptime in Aseptic Processing BACK TO EBOOK

of Pharmaceutical Liquids with Blow/Fill/Seal
erate. Also referred to as uptime. Factors like equipment ment and operating aspects of the pharmaceutical line
cleaning, changeovers, equipment breakdown and preven- to arrive at a percentage. In pharmaceutical packaging
tative maintenance are conditions that will influence the these machines may include sorters, fillers, cappers, label-
OEE metric rating for Availability. ers, cartoners, case packers and palletizers. Each machine
would have its own systems and cycles. An OEE rating can
Performance represents the speed at which the process or be determined for each machine on the line, and/or for the
machine runs as a percentage of its designed speed. Fac- entire line.
tors that influence the OEE rating for Performance include
temporary equipment stops from jams, machine cycle set- Blow/Fill/Seal Processing of
tings, designated speed and product throughput. Aseptic Pharmaceutical Liquids
One area of pharmaceutical manufacturing that has made
Quality in the OEE metric represents the good products significant gains in Overall Equipment Effectiveness is in the
produced as a percentage of the total units started. This packaging of aseptic pharmaceutical liquids with Blow/Fill/
OEE rating is influenced by rejected products. More specif- Seal (B/F/S) technology. From the perspective of OEE, and
ically, those rejects caused by equipment or personnel, and focusing on uptime and changeover time improvement,
those rejects separated into rework and scrap. aseptic Blow/Fill/Seal machines present highly efficient sys-
tems for production of sterile liquid products.
Each of these metrics are then factored at a percentage of
operation compared to the ideal operating condition. For The aseptic Blow/Fill/Seal system has proven to improve
example, a given line may have an Availability factor of 86.7 product integrity and better ensure patient safety over
percent, a Performance rating of 93.0 percent, and a Quali- traditional aseptic processing procedure. As a result, the
ty factor of 95.0 percent. The OEE would then be comput- United States Food and Drug Administration and the Unit-
ed by multiplying 86.7% x 93.0% x 95.0%, for a composite ed States Pharmacopoeia now characterize modern B/F/S
OEE metric of 76.6 percent for that line. technology as an ‘advanced aseptic process’, indicating its
use as a preferred technology
Typically, each metric would factor in many pieces of equip- over other aseptic systems, and
44
SPONSORED BY

a better solution for the sterile, aseptic processing of phar- ing and sterilizing of containers, separate processing steps
maceutical liquids. and equipment for filling and sealing, and end processing
handling such as labeling.
B/F/S is a self-contained process. The consolidation of pro-
cess steps results in streamlined efficiency for the entire liq- In pharmaceutical processing, it is the filling process that
uid filling and packaging production process. The technol- determines the line speed. System delays and downtime
ogy integrates a three-step process of blow molding, sterile caused by such manually-dependent processes in aseptic
filling and hermetic sealing in a continuous, highly-automat- packaging can have significant throughput and cost conse-
ed operation. Unique to aseptic B/F/S systems compared quences which depress OEE.
to traditional aseptic processing is their capability for rapid
container closure and minimized aseptic interventions. Fur- Conversely, automating the aseptic process can have a
ther, B/F/S incorporates the use of recyclable plastic resins. sizable impact on improving uptime. The most advanced
Low-density polyethylene, high-density polyethylene and aseptic B/F/S systems are quite automated, compared to
polypropylene, used to produce aseptic containers for intraditional aseptic processing. These B/F/S machines are
jectables, ophthalmics, biologicals and vaccines are gener- designed to require minimum human access while operat-
ally considered inert by the FDA. ing in Class-100 environments. Various in-process control
parameters utilizing the latest generation of fully-system-in-
Simplified B/F/S Machine Design Improves Uptime tegrated PLCs, control and monitor container weight, fill
Traditional aseptic procedures for packaging pharmaceuti- weight, wall thickness, isolation of visual defects and other
cal liquids involve multiple steps in the handling and ma- factors, facilitating optimized system function.
nipulation of the material, containers and sterilization filling
processes with human intervention, and therefore have With the latest generation of Blow/Fill/Seal machines, as ex-
a heightened potential for system downtime and prod- emplified in the ASEP-TECH® B/F/S system from Weiler En-
uct contamination during processing. Manual processing gineering, the forming, filling and sealing steps are achieved
steps for conventional aseptic processing include receiving, in one unit operation – the cycle
inspection and warehousing of incoming containers, wash- being completed within seconds.
45
SPONSORED BY

Such automation eliminates unneeded manpower and re- mats. The incorporation of a sterile tip-and-cap, a rubber
duces the risk to product integrity. These B/F/S machines al- stopper or a multi-entry insert into the B/F/S package offers
low very efficient processing speed and short machine cycle added flexibility in container design and drug delivery
times. They minimize the time required to perform complex methods, as well as enhanced sterility safety.
tasks and increase efficiency in process operations. Such au-
tomated process technologies improve product quality and Quick Changeovers
consistency, and increase production throughput, substan- Packaging equipment changeovers present one of the most
tially supporting Overall Equipment Effectiveness. costly and time-consuming activities within pharmaceutical
manufacturing. Indeed, changeover adaptability remains
Flexibility of B/F/S Container Design the most critical packaging machine feature, with sizable in-
Optimizes Machine Operation fluence on OEE. The versatility of packaging equipment to
B/F/S allows considerable flexibility in the design of con- facilitate rapid changeovers has never been more important
tainers, adding to improved OEE. Pre-molded, pre-steril- in pharmaceutical manufacturing, and aseptic Blow/Fill/Seal
ized components, called inserts, can be easily integrated systems exemplify this initiative.
into the basic container. These inserts, including items such
as rubber and silicone stoppers, and tip-and-cap dropper Many B/F/S machines are configured to produce more than
units for eye drop containers used to deliver a calibrat- one bottle shape or format. This makes it easy to change
ed drop, are attached to the container after the blowing over from one container size to another. A B/F/S machine
and filling process, prior to sealing. These improvements might produce a family of 2ml, 3ml and 5ml containers,
streamline the packaging process, eliminating the need for then switch to a family of 5ml, 10ml and 15ml containers,
secondary packaging. Labeling is not needed, since the or to one of 10ml, 15ml and 20ml containers, moving from
molds can be engraved with product information, which one to the other with relative ease of machine set-up.
avoids an additional process step. This is ideal for manufacturers, such as those performing
contract packaging of aseptic liquid pharmaceutical solu-
Advanced aseptic B/F/S containers and ampoules can be tions, because of their need for
manufactured to deliver precise dosing in disposable for- changeover flexibility. ASEP-
46
SPONSORED BY

TECH® B/F/S systems from Weiler are capable of produc- high-volume aseptic process lines into multiple, smaller
ing containers ranging in size from 0.1ml to 1,000ml at Blow/Fill/Seal lines. The use of smaller machines provides
production rates of 15,000 units per hour, depending on enhanced production flexibility and improved efficiency. In
container configuration. the event that one of the lines goes down for maintenance
or repair, it will not stop the entire production throughput.
The growing usage of biologics is demanding packaging Products can be easily ‘campaigned’ with B/F/S, using one
in different formats. These drug products usually require line with one container geometry for multiple products.
smaller process runs and are typically heat sensitive. Many Since B/F/S is ideally suited for these ‘campaigns’ due to
of these new biotechnological drugs do not withstand ter- quick changeovers, it is a natural pick for manufacturers
minal sterilization with steam or irradiation, and so are best desiring to optimize OEE.
treated aseptically. More advanced B/F/S machines are
designed so they can handle these heat sensitive products Efficient Utilization of Time
without adversely affecting product quality. Modern B/F/S system design embodies OEE initiatives,
being focused on changeover simplicity and flexibility, and
The B/F/S process offers outstanding versatility for multi- permitting shorter runs, increased uptime and maximized
ple container designs. A unique design feature offered on throughput.
the ASEP-TECH® B/F/S systems, for example, permits the
insertion of a secondary delivery device into the container Blow/Fill/Seal machine efficiency rates very high. More
prior to the final hermetic sealing step. This feature can be advanced Blow/Fill/Seal machines can approach 99 per-
suspended, however, without requiring significant equip- cent uptime efficiency, significantly higher than traditional
ment changeover. This allows the production of standard aseptic processing, which is plagued with slow-downs, in
containers without inserts on the same machine with only a part because of manual interventions. B/F/S also performs
simple recipe and tooling change. noticeably higher than the peak 70 percent operating
efficiency of the world’s most streamlined pharmaceutical
To further minimize potentials of system downtime, some manufacturing facilities.
pharmaceutical manufacturers are now segmenting their
47
SPONSORED BY

Improved uptime, minimized changeover time and efficient The company uses the latest technological advances in
OEE are key factors that have influenced the acceptance equipment design and systems to ensure the highest level
of aseptic Blow/Fill/Seal. These are critical functions for of quality in the production of sterile liquid products. Its
achieving improved product quality and profitability in the equipment must meet demanding corporate, scientific,
packaging of aseptic pharmaceutical liquids. regulatory and end-user requirements. These application
challenges are met through the offering of several machine
About Weiler Engineering: models designed to manufacture containers ranging in size
Weiler Engineering is a worldwide provider of aseptic Blow/ from 0.1 ml to 1,000 ml at production rates of up to 15,000
Fill/Seal custom packaging machinery for pharmaceutical units per hour, depending on container configuration.
and healthcare applications. Based in Elgin, Illinois, and
founded in 1959, Weiler’s proprietary Blow/Fill/Seal system To reach Weiler Engineering, please contact Chuck Reed;
is the culmination of 40 years of innovation in machine 1395 Gateway Drive, Elgin, Illinois 60124; Phone 847-697-
design and sterile process development, producing a 4900; email solutions@weilerengineering.com;
highly advanced aseptic liquid packaging system. Its ASEP- www.weilerengineering.com
TECH® Blow/Fill/Seal technology integrates blow molding,
sterile filling and hermetic sealing in one continuous opera-
tion to produce aseptically manufactured products.
48
SPONSORED BY
Streamlined Blow/Fill/Seal Insertion BACK TO EBOOK
Technology Increases Flexibility and Safety in

Aseptic Packaging of Pharmaceutical Liquids
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 that facilitates these goals is the advance in insertion
to be an ideal system for the creation of a wide vari- technology. The latest generation of aseptic B/F/S
ety of container shapes and sizes used for packaging machines incorporates dedicated isolators adapted
sterile pharmaceutical liquids. B/F/S is well suited to specifically for insertion applications. These modular
producing closed aseptic containers, like injectable insertion isolators are typically located outside of the
products, that need to be opened under critically classified machine room, separate from but directly
sterile conditions within a clinical environment such as connected to the B/F/S unit through a transfer tunnel.
a hospital, as well as sterile products opened by in- The isolator and tunnel are typically sterilized with
dividuals in work-a-day environments like ophthalmic vaporized hydrogen peroxide and the Class 100 envi-
dropper units. These products must meet the man- ronment within it is maintained by HEPA filtration. This
dates of drug manufacturers and government regula- new addition to the aseptic B/F/S system has not only
tors that require sterile products that will stay sterile streamlined the insertion process, but has provided a
until the time of use. Manufacturers also desire the higher level of sterility assurance for products with tip-
most cost-efficient packaging systems to achieve these and-caps and rubber/silicone
ends without any loss of product integrity. One of the stoppers inserted under asep-
more recent improvements in aseptic B/F/S processing tic conditions.
49
SPONSORED BY
CONTINUED Streamlined Blow/Fill/Seal Insertion Technology Increases BACK TO EBOOK

Flexibility and Safety in Aseptic Packaging of Pharmaceutical Liquids
Insertion Applications in Advanced Aseptic B/F/S molding resins used in B/F/S processing have received
Although glass has been the traditional choice for international acceptance as suitable for pharmaceuti-
packaging sterile pharmaceutical liquid products, cal liquids applications. These inert materials do not
B/F/S-produced plastic containers have emerged as contain additives, have low water vapor permeability,
a viable alternative during the past few decades, and and are easy and safe to handle in critical care envi-
particularly with the recognition by the U.S. Food and ronments such as hospitals. Further, temperature-sen-
Drug Administration of B/F/S as an advanced aseptic sitive biological and protein-based products can be
process, indicating it as a preferred technology over processed in advanced B/F/S machines, providing a
other aseptic systems. level of enhanced sterility assurance.
Unlike glass, plastic containers are shatter-proof. Glass For these reasons the interest in B/F/S-produced plas-
vials are subject to breakage, both in transit and while tic containers, and particularly injectable product con-
being administered. Handling glass containers always tainers, is continuing to grow within the pharmaceuti-
involves a certain amount of risk of lacerations and cal industry.
glass splinters, such as with small volume parenterals,
where glass ampoules can generate a fine array of Along with the growing interest in B/F/S plastic con-
small glass particles during opening. tainers, the application of aseptically-produced B/F/S
containers with inserts has also become increasingly
A critical aspect of B/F/S technology is its pyro- popular. Advanced B/F/S machine designs allow the
gen-free molding of containers and ampoules. B/F/S capability to incorporate the addition of pre-molded,
processing resins, polyethylene and polypropylene, pre-sterilized components (inserts) into the basic con-
used to produce aseptic containers for injectables, tainer. These inserts, including items such as rubber
ophthalmics, biologicals and vaccines are generally and silicone stoppers, and tip-
considered inert by the FDA, and many of the blow and-cap dropper units for eye
50
SPONSORED BY

drop containers (used to deliver a calibrated drop), are Aseptic B/F/S-produced small-volume parenterals (SVP),
attached to the container after the blowing and filling such as those used for local anesthetics, vitamins, vaccines
process, prior to final sealing step. The application of and other standard injectable products, can be manufac-
inserts has allowed B/F/S technology to advance and tured with a twist-off-opening feature. They can also be
expand into product markets which were previously combined with a controlled-diameter form in the top to
accommodate needle-less spikes. Luer locks or luer-slip fits
unavailable, such as intravenous drug administration,
can also be provided for making leak-free connections. For
solution irrigation and ophthalmic dropper units. 2 to 5 mL small- volume parenterals, syringes can be con-
nected directly to the ampoules without a needle, creating
With ophthalmics, the B/F/S insert process enables an inherently safer packaging solution.
increased efficiency and sterility control in the pro-
cessing of expensive drug formations for treatment B/F/S-produced, one piece, plungerless sterile syringes
of glaucoma and other eye diseases. Other types (designed for pre-filling) for use in flushing hospital equip-
of sterile inserts can be incorporated into the basic ment such as catheters, are available for replacing tradi-
B/F/S-produced container as well, such as top geo- tional two-piece plunger-type syringes. The B/F/S syringe
metrics for both bottles and ampoules that can include provides an offset chamber for trapping air, and preventing
a multi-entry rubber stopper or a controlled diameter it from being dispensed during drug delivery.
injection-molded insert, useful where multiple admin-
Advanced B/F/S insertion processes can also incorporate
istration of a drug is required. The stopper would
tamper-evident features for multi-dose container closures,
typically be an FDA-approved, rubber or silicone insert offering added security.
that would be placed inside the bottle or parenteral.
Then, at the point of delivery the nurse would stick a Advanced Insertion Isolation Technology
needle through the stopper and extract the fluid, or if The latest generation of Blow/Fill/Seal machines use a
it is a vascular flush, the nurse would insert it into the modular design, integrating duo
patient’s IV set. Class 100-environment manu-
51
SPONSORED BY

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

for example, requires filling and sealing to be carried out Ultrasonic KleenKut® technology can be used to cut the
in a Class 100 environment and necessitates considerable molten parison at ambient temperature, drastically reduc-
validation efforts. Both the B/F/S machine and the inser- ing non-viable smoke particles that are generated by tradi-
tion isolator do not need to be housed in a Class 100 area tional hot knife cutting. The process reduces particulates in
because their activities are protected within the machines the cutting area by 99 percent. Non-viable particles 0.3µm
themselves. This protection considerably reduces the to 10µm in size are significantly reduced in quantity com-
scope of validation requirements. pared with the volume of particles produced during the use
of hot-knife cut-off mechanisms.
Sterility and particulate matter are two of the most critical re-
quirements for aseptically-produced products, and advanced Expanding Use of Blow/Fill/Seal Insertion Technology
B/F/S and insertion isolation technology offer distinct advan- Advanced aseptic B/F/S containers and ampoules can de-
tages over earlier systems. This includes maintaining precise liver precise dosing in disposable formats. The incorpora-
control over differential air pressure between the isolator, tion of a sterile tip-and-cap, a rubber stopper or a multi-en-
the insert transport and the B/F/S nozzle shroud. Both the try insert into the B/F/S package offers added flexibility
isolator and the B/F/S system are equipped with HEPA air in container design and drug delivery methods, as well as
showers to assure a Class 100 environment under dynamic enhanced sterility safety. These benefits are continuing to
conditions in the isolator, tunnel and nozzle shroud area. push the acceptance and use of advanced aseptic B/F/S
technology, particularly into injectable product areas and
It has been well documented that in the B/F/S process, biologics – where proteins and other complex solutions
non-viable particles primarily originate from the electrical- have brought B/F/S technology to the forefront.
ly heated cut-off knife contacting the molten parison, and
that better control of non-viable particulates will provide The B/F/S process offers outstanding versatility for multiple
enhanced sterility assurance for the Blow/Fill/Seal process. container designs. A unique design feature of the ASEP-
The more advanced B/F/S systems use additional technolo- TECH® B/F/S systems, for example, permits the insertion
gy in response to FDA concern over particulate contamina- process to be suspended without
tion during B/F/S fabrication. requiring significant equipment
53
SPONSORED BY

changeover. This feature allows the production of standard is the culmination of 40 years of innovation in machine
containers without inserts to be produced on the same ma- design and sterile process development, producing a
chine with a simple recipe change. highly advanced aseptic liquid packaging system. Its ASEP-
TECH® Blow/Fill/Seal technology integrates blow molding,
As the use of advanced aseptic Blow/Fill/Seal processes sterile filling and hermetic sealing in one continuous opera-
broaden, insertion technology will become more important tion to produce aseptically manufactured products.
as drug producers continue to seek new delivery methods
for breakthrough drugs. The company uses the latest technological advances in
equipment design and systems to ensure the highest level of
About the Author: quality in the production of sterile liquid products. Its equip-
Andrew W. Goll is Technical Sales Manager for Weiler Engi- ment must meet demanding corporate, scientific, regulatory
neering, Inc., responsible for technical support for the com- and end-user requirements. These application challenges
pany’s customers worldwide. He has over 18 years of expe- are met through the offering of several machine models de-
rience in the Blow/Fill/Seal community including research signed to manufacture containers ranging in size from 0.1 mL
and development, design engineering, and contract and to 1,000 mL at production rates of up to 15,000 units per
generic manufacturing plant operations. He is a member hour, depending on container configuration.
of the Parenteral Drug Association (PDA) and International
Society for Pharmaceutical Engineering (ISPE). Goll holds a To reach Weiler Engineering, please contact Chuck Reed,
Bachelor of Science degree in business administration and Director, Sales & Marketing; 1395 Gateway Drive, Elgin,
a Master of Business Administration degree. Illinois 60124; Phone 847-697-4900;
email solutions@weilerengineering.com;
About Weiler Engineering: www.weilerengineering.com
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, Weiler’s proprietary Blow/Fill/Seal system
54

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E-BOOK

04 Historical/Current Regulatory Viewpoint

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

12 Resin Choices/Examples of Container Cost Savings

Blow/Fill/Seal (B/F/S) aseptic processing in parenteral manufacturing

The automated nature of the process leads to:

Limit Human Intervention and Effectively Reduce Airborne Microbial

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

• Current technological advances are superior to legacy systems

What kind of containers may be produced?

CLICK THROUGH THE NEXT 4

B/F/S Inspiration Image Gallery 1/4

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

B/F/S Inspiration Image Gallery 3/4

B/F/S Inspiration Image Gallery 4/4

Herbal/Oral Nutraceuticals Douche, Enema

Irrigation/wound cleaner bottles Beverage electrolyte, sport drinks-High Res

Drivers Affecting Innovation and the

1. Current production issues with particulates in glass containers 31.6%

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%

Source: PDA Europe Conference on Parenteral Packaging, March 2015.

Resin Choices for B/F/S Processing

• Multi-dose use bottles

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

Advances in Aseptic Blow/Fill/Seal BACK TO EBOOK

Processing of Pharmaceutical Liquids Improve

CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of BACK TO EBOOK

CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of BACK TO EBOOK

CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of BACK TO EBOOK

CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of BACK TO EBOOK

CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of BACK TO EBOOK

CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of BACK TO EBOOK

About Weiler Engineering: and end-user requirements. These application challenges

The company uses the latest technological advances in

Aseptic Blow/Fill/Seal: A Sustainable Process BACK TO EBOOK

for Packaging Pharmaceutical Liquids

CONTINUED Aseptic Blow/Fill/Seal: A Sustainable Process BACK TO EBOOK

Implementing energy-efficient practices and technologies

CONTINUED Aseptic Blow/Fill/Seal: A Sustainable Process BACK TO EBOOK

CONTINUED Aseptic Blow/Fill/Seal: A Sustainable Process BACK TO EBOOK

CONTINUED Aseptic Blow/Fill/Seal: A Sustainable Process BACK TO EBOOK

CONTINUED Aseptic Blow/Fill/Seal: A Sustainable Process BACK TO EBOOK

CONTINUED Aseptic Blow/Fill/Seal: A Sustainable Process BACK TO EBOOK

CONTINUED Aseptic Blow/Fill/Seal: A Sustainable Process BACK TO EBOOK

CONTINUED Aseptic Blow/Fill/Seal: A Sustainable Process BACK TO EBOOK

Improving Process Quality of Pharmaceutical BACK TO EBOOK

Liquids – Aseptic Blow/Fill/Seal Technology

CONTINUED Improving Process Quality of Pharmaceutical Liquids – BACK TO EBOOK

CONTINUED Improving Process Quality of Pharmaceutical Liquids – BACK TO EBOOK

CONTINUED Improving Process Quality of Pharmaceutical Liquids – BACK TO EBOOK

CONTINUED Improving Process Quality of Pharmaceutical Liquids – BACK TO EBOOK

CONTINUED Improving Process Quality of Pharmaceutical Liquids – BACK TO EBOOK

Microbial and Particulate Integrity spores and endotoxin-contaminated polymer granules.

CONTINUED Improving Process Quality of Pharmaceutical Liquids – BACK TO EBOOK