blow/fill/seal - healthcare packaging that parenterals, injectables, ophthalmic solutions, and...

BLOW/FILL/SEAL: AN ADVANCED ASEPTIC PACKAGING TECHNOLOGY

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BLOW-FILL-SEAL: AN ADVANCED ASEPTIC PACKAGING TECHNOLOGY

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TABLE OF CONTENTS

Machine Operation

Historical/Current Regulatory Viewpoint

Process Advantages

What kind of containers may be produced?

B/F/S Inspiration Image Gallery

Drivers Affecting Innovation and the Use of B/F/S for Legacy and New Drugs.

Resin Choices/Examples of Container Cost Savings

Topics of Concern

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 HERE TO VIEWCLICK HERE TO VIEW


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Blow/Fill/Seal (B/F/S) was originally developed in Germany and has been present in the U.S. since 1968

Technology Evolution• Initial thrust in the U.S. was centered around food and dairy products

(juices, fruit drinks, milk).• Non-sterile medical devices (douche and enema)• Sterile devices, diagnostics and pharmaceuticals

(respiratory diluents, RT drugs, ophthalmics)• In 1993 the first biologic was approved for packaging with B/F/S technology• General trend towards the manufacturing of injectable drugs

• 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

Historical

Current Regulatory Viewpoint

Provide Critical Advantages for

Sustainable Initiatives for Processing and

Packaging Pharma Liquids.

CLICK HERE TO VIEWCLICK HERE TO VIEW


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Why Do Companies Typically Use B/F/S Systems?• Flexibility in Packaging Design• Low Operating Cost• High Degree of Sterility Assurance• Small Space Requirement• Limited Component Inventory• Limited Number of Operators Required

Thermoplastic resin is extruded into a tubular shape called a parison.

When the parison reaches the proper length, the mold indexes, pinching the bottom of the parison closed. The top of the parison is held open while the parison is cut.

The mold is conveyed into position under the blowing/filling nozzle assembly. The nozzle is lowered into the parison, forming a seal with the neck of the mold. The container is formed by vacuum or assisted by blowing with sterile filtered air, expanding the parison against walls of the integrally cooled mold cavity. While in position, the sterile air is vented from and sterile liquid product is metered into the container through the fill nozzle.

The fill assembly retracts and separate sealing molds close to form the top, hemetically sealing the container.

The mold opens and formed, filled and sealed container is conveyed out of the machine.

Process Advantages

The Process

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• Vials with inserted tip / cap• Vials with a twist-off and re-closeable• Multi-dose use bottles• Eye wash and contact lens solution• Unit Dose Injectable

• Respiratory care• Electrolyte and Sport Drinks• Rubber stopper insertion• Euro Cap• Spike Top

What kind of containers may be produced?

CLICK THROUGH THE NEXT 4 PAGES TO SEE 16 DIFFERENT

USAGE EXAMPLES

B/F/S INSPIRATION IMAGE GALLERY


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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-SVP using insertion technologyInjectable-Large volume parenterals


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Injectable-LVP design options Eye Care-Spike top containers in 5-20ml

Eye Care-eyewash, contact lens solution bottlesEye Care-Tip/cap multi dose vialsCare-Tip/cap multi dose vials 5-20ml


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Eye Care-Unit dose for one time ophthalmic use Biologicals vial pack

Respiratory Therapy-R/T unit dose 0.5 - 3ml vials in LDPE

Respiratory Therapy-nebulizer and PP bottle, 500 ml


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Herbal/Oral Nutraceuticals Douche, Enema

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


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Which one of the following considerations would most likely lead you to develop your NEW, INNOVATIVE DRUG PRODUCT in B/F/S technology?

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

2. Flexibility with container design (geometry, unit dose format, etc.) 31.6%

3. Desire for more user friendly drug delivery system 23.7%

4. Improved stability of the product in plastic 13.2%

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

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%

Drivers Affecting Innovation and the Use of B/F/S for Legacy and New Drugs.

A comparison of traditional packaging

v. Blow/Fill/Seal technology



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• Depends on stability of products

• Multi-dose use bottles - LDPE, HDPE, P.P. - Low, Medium and High Density Polyethylene. Barrier properties improve

as density increases, clarity of container improves as density decreases - Polypropylenes. Excellent barrier properties and good clarity

and high temperature terminal sterilization

3ml Vial• Cost of Conventional Vial with Closure only ......................• Cost of B/F/S vial incl. all operating costs .....................• Savings Per Bottle ...........................................................• Savings Per Year ..........................................................

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.

$0.07($0.036)

$0.034$1.85MM

Resin Choices for B/F/S Processing

Examples of Container Cost Savings

Maximize Uptime, Minimize Changeover

time and increase overall equipment

effectiveness (OEE)



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• 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.

Topics of concern


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• 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.

Topics of concern CONTINUED

Blow/Fill/Seal Insertion Technology Increases Flexibility for Drug DeliveryAdvanced 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 HERE TO VIEWCLICK HERE TO VIEW


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Weiler Engineering, Inc.

Weiler Engineering, Inc. is a world leader in providing sterile, aseptic liquid packaging equipment for pharmaceutical and healthcare applications. Weiler is committed to the highest standards of excellence and to further expanding products and systems to enhance patient care.

Weiler’s proprietary ASEP-TECH® Blow/Fill/Seal packaging machines produce shatterproof, durable, sterile aseptically packaged products in one uninterrupted operation on a single, compact machine frame without human intervention, ensuring that parenterals, injectables, ophthalmic solutions, and respiratory drugs reach the marketplace in the most sterile, cost-effective manner possible—every time.

The ASEP-TECH® System from Weiler is the culmination of more than 50 years of innovation in machine design and sterile process development, resulting in the most advanced aseptic liquid packaging process available today through the application of Blow/Fill/Seal technology. Our Vision - Building quality equipment profitably, Fostering innovation and Satisfying customers.

About the Author

Chuck Reed has extensive experience in specialized equipment design and manufacture, process technology and pilot plant design and construction.

He is a 15+ year member of both PDA and ISPE, is past Chairman of the ISPE Packaging Community of Practice and continues to serve on this COP steering committee. He is an author for the ISPE Packaging, Labeling and Warehousing (PACLAW) Baseline Guide. He is currently Chairman of the PDA Blow/Fill/Seal Interest Group, member of the PDA Blow/Fill/Seal Technical Report Task Force and a chapter author in the PDA 2-volume Aseptic Processing text. Mr. Reed holds a Bachelor of Science in Chemical Engineering from Clarkson University and a Master of Science in Management from National Louis University.

Email [email protected] to contact Chuck.

1395 Gateway Drive, Elgin, IL 60124PHONE: 847/697-4900 - FAX: 847/697-4915Website: www.asep-tech.com

mailto:[email protected]

www.asep-tech.com

BLOW-FILL-SEAL: AN ADVANCED ASEPTIC PACKAGING TECHNOLOGY APPENDIX

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BLOW/FILL/SEAL: AN ADVANCED ASEPTIC PACKAGING TECHNOLOGYAPPENDIX


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Advances in Aseptic Blow/Fill/SealProcessing of Pharmaceutical Liquids ImproveProduct Integrity and Patient Safety

Aseptic Blow/Fill/Seal (B/F/S) systems for the process-ing of pharmaceutical liquids have experienced rapid and growing acceptance by the pharmaceutical indus-try over the past 20 years. This has been accelerated by enhancements made to aseptic B/F/S processes based on pharmaceutical industry input and to ac-commodate the requirements of regulatory agencies. These enhancements were designed to improve prod-uct integrity and help ensure patient safety. As a result, the United States Food and Drug Administration and the United States Pharmacopoeia now characterize modern B/F/S technology as an “advanced aseptic process”, indicating its use as a preferred technology over other aseptic systems and a better solution for the sterile, aseptic processing of pharmaceutical liquids. Aseptic B/F/S systems offer a unique combination of

flexibility in packaging design, low operating cost and a high degree of sterility assurance. Due to its design and functionality, B/F/S processing inherently produces very low levels of particulate matter, and much of the potential for microbial contamination in its critical areas is mitigated by the absence of human intervention in these areas.

Microbial contamination is a serious issue for compa-nies manufacturing liquid pharmaceutical formulations. Such liquids are ideal growth areas for bacteria like Sal-monella, Escherichia coli and Staphylococcus microbes that have been found in various liquid drug products. A supposedly sterile, but con-taminated product may result in deterioration of the drug

The latest improvements in aseptic Blow/Fill/Seal technology are providingmore streamlined automation of critical B/F/S processing areas, while limiting humanintervention and effectively reducing airborne microbial bioburden and particulate

by Chuck Reed, B.Sc/MS, Director, Sales & Marketing, Weiler Engineering, Inc.

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CONTINUED Advances in Aseptic Blow/Fill/Seal Processing of Pharmaceutical Liquids Improve Product Integrity and Patient Safety

and loss of potency, and with parenterals can cause py-rogenic reactions after administration to patients. The majority of liquid drug product contamination over the past several decades has come about from products produced in conventional (non-B/F/S) aseptic process-ing facilities. In conventional aseptic processing, the drug product, container and closure are subjected to sterilization processes separately, and then brought together. There is no further processing to sterilize the product after it is in its final container, therefore it is critical that containers be filled and sealed in an ex-tremely high-quality environment.

Automation Upgrades Improve SterilityAssurance in the B/F/S “Critical Zone”Aseptic B/F/S technology integrates blow molding, sterile filling and hermetic sealing in one continuous operation to produce aseptically manufactured pharmaceutical liquidproducts. Unique to aseptic B/F/S systems compared to traditional aseptic processing, is its capability for rapid con-tainer closure and minimized aseptic interventions.

The most advanced aseptic B/F/S systems are quite auto-mated, designed to require minimum human access and reduce risk to the product’s integrity, while operating in a

classified environment. Various in-process control param-eters, such as container weight, fill weight, wall thickness and visual defects provide information that is monitored and facilitates ongoing process control. Its containers are formed from a thermoplastic granulate, filled with a liquid pharmaceutical product and then sealed in a continuous, integrated and totally automated sequence – the critical fill-zone area is shrouded under a continuous flow of posi-tive-pressure sterile filtered air. The B/F/S cycle is complet-ed within seconds. This reduces the amount of components contacting the product, and limits operator intervention particularly with system changeovers and cleaning.

Recent B/F/S equipment designs employ the use of spe-cialized measures to reduce particle levels and minimize potential microbial contamination of the exposed product in the plastic extrusion and cutting zone. Non-viable par-ticles generated during the plastic extrusion, cutting, and sealing processes are thoroughly controlled.

Provisions for carefully controlled airflow protect the prod-uct by forcing created particles outward while preventing any inflow from the adjacent environment. This B/F/S zone of protection is continually supplied with HEPA-filtered air, by an air shower device (shroud). Air in the critical filling zone

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meets Class 100 (ISO 5) microbiological standards during operations. Sterile air management within this critical zone is typically verified through environmental monitoring for the presence of non-viable particulates.

Non-viable particles in the B/F/S process primarily origi-nate from the electrically heated cut-off knife contacting the molten parison (an extruded tube of hot plastic resin through which sterile support air passes during the extru-sion sequence). Past attempts to manage non-viable partic-ulate generation in this zone of protection were targeted to the removal of particles after they were produced. Included in recent improvements was the development of parison shrouding, which produces a controlled air environment byemploying an exhaust blower system with differential pres-sure controls in conjunction with containment ductwork in the parison cut-off area, to siphon away smoke created by the hot knife – a heated high-resistance wire.

A new technology was introduced to eliminate the gener-ation of the parison-cutting smoke altogether – the Kleen-Kut® parison cut-off mechanism. The device is an automat-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

more than 99 percent. The KleenKut mechanism assures that non-viable particles 0.3μm to 10μm in size are significantly reduced in quantity compared with the volume of particles produced during the use of a hot-knife cut-off mechanism.

The FDA’s 2004 Guidance for Industry Sterile Drug Products Produced by Aseptic Processing states that the design of equipment used in aseptic processing should limit thenumber and complexity of aseptic interventions by person-nel. Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product, container-closures or the surrounding environment. It states further, that airborne contamination is directly related to the number of people working in a cleanroom and the level of congregation by personnel in areas where critical aseptic ma-nipulations are performed.

Any intervention or stoppage during an aseptic process can increase the risk of contamination. The design of equipment used in aseptic processing should limit the number and com-plexity of aseptic interventions by personnel.


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Reduced Airborne Microbial Bioburden in Recent Challenge Study of Advanced B/F/S SystemChallenge studies on aseptic B/F/S systems have been performed over the past 20 years which have correlated the microbial bioburden of environmental air in a B/F/S fill-roomto the potential contamination rate of product which is filled on machines in those rooms. These studies have led to an increased understanding of the capabilities of aseptic B/F/Stechnology in the production of sterile products.

B/F/S system manufacturers should base their product de-velopment on such studies, including materials testing spe-cifically for microbial challenges, which have been support-ed with scientific evidence that the researched machines function within the standards of accredited agencies.

One of the more recent B/F/S challenge studies was con-ducted in 2004 by Cardinal Health, Inc. and Air Dispersions, Ltd. entitled “Evaluation of Blow/Fill/Seal Extrusion through processing of Polymer Contaminated with Bacterial Spores and Endotoxin”, a study that was carried out to further the understanding of the extrusion process and its impact upon the quality of Blow/Fill/Seal product. Controlled challeng-es were conducted to the extrusion system, comprising low-density polyethylene granulate contaminated with Ba-cillus atrophaeus endospores and Escherichia coli bacterial

endotoxin. The challenge was performed with an advanced aseptic B/F/S system supplied by Weiler Engineering, Inc.

Sterility of B/F/S polymeric containers, materials and pro-cesses is validated by verifying that time and temperature conditions of the extrusion, filling and sealing processes areeffective against endotoxins and spores. This report states “The extruder challenge studies, employing spore polymer and endotoxin polymer, have provided definite evidence for polymer extrusion having the capability to produce vials ‘free’ of viable microorganisms and possessing acceptable endotoxin levels.”

The challenge study demonstrates a uniform capability of achieving high sterility assurance levels (10-6 SAL) through-out the entire process. Even higher sterility assurance lev-els, approaching 10-8 SAL, have been achieved using high levels of airborne microbiological challenge particles.

A critical aspect of B/F/S technology is its pyrogen-free molding of containers and ampoules. Extensive experi-ments in this challenge study confirm the efficacy of theB/F/S extrusion process, having been performed using high levels of spores and endotoxin-contaminated polymer granules. Results demonstrated fractional spore contamination


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levels of less than 1x10-6, and a three-log reduction in endotoxins with the probability of a non-sterile unit (PNSU) approaching one in one million.

Expanded Options for B/F/S Packaging andDelivery Solutions of Pharmaceutical LiquidsB/F/S processing resins, polyethylene and polypropylene, used to produce aseptic containers for injectables, ophthal-mics, biologicals and vaccines are generally considered in-ert by the FDA, and many of the blow molding resins used in B/F/S processing have received international acceptance as suitable for pharmaceutical liquids applications. These inert materials do not contain additives, have low water va-por permeability, and are easy and safe to handle in critical care environments such as hospitals.

Of particular interest within the pharmaceutical industry, is the use of plastic material for the B/F/S production of small volume parenterals. Plastic ampoules offer significant ad-vantages over rubber-stopper glass vials. There is the safety issue – glass vials are subject to breakage, both in transit and while being administered. Handling glass containers always involves a certain amount of risk of lacerations and glass splinters. Glass ampoules generate a fine array of small glass particles during opening. Glass is typically trans-ported in cardboard boxes that can contain mold spores,

such as Penicillin sp. and Aspergillus sp., as well as bacteria like Bacillus sp. Paper, also used in the shipping of glass, can also contain mold spores. The rubber closures used on the glass containers can have mold contamination.

Aseptic B/F/S-produced small-volume parenterals, such as those used for local anesthetics, vitamins, vaccines and oth-er standard injectable products, can be manufactured with a twist-off-opening feature. They can also be combined with a controlled-diameter form in the top to accommodate needle-less spikes. Luer locks or luer-slip fits can also be provided for making leak-free connections. For 2 to 5 mL small volume parenterals, syringes can be connected direct-ly to the ampoules without a needle, creating an inherently safer packaging solution.

B/F/S-produced, one piece, plungerless sterile syringes (designed for pre-filling) for use in flushing hospital equip-ment such as catheters, are available for replacing tradi-tional two-piece plunger-type syringes. The B/F/S syringe provides an offset chamber for trapping air, and preventing it from being dispensed during drug delivery.


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The increased focus on biologics, proteins and other com-plex solutions has brought B/F/S technology to the fore-front. These pharmaceutical products often cannot with-stand exposure to high temperatures for extended periods of time without degradation of their active components, making conventional terminal sterilization an unaccept-able method to produce a “sterile” product. Temperature sensitive biological and protein-based products can be processed in advanced B/F/S machines, providing a level of enhanced sterility assurance. Bulk sterilization, steriliza-tion by gamma or e-beam irradiation, or filter sterilization followed by direct packaging utilizing the B/F/S process are used successfully for these types of products. B/F/S is demonstrating less than a one-degree C temperature rise in a liquid pharmaceutical which is packaged in a 5 mL poly-ethylene vial.

Advanced B/F/S technology can also include the applica-tion of insertion technology to permit the incorporation of a sterile tip and cap insert into the Blow/Fill/Seal package toproduce a calibrated drop. This process enables increased efficiency and sterility control in the processing of expen-sive drug formations for treatment of glaucoma and other eye diseases. Other types of sterile inserts can be incorpo-rated into the basic B/F/S-produced container as well. Top geometrics for both bottles and ampoules can include a

multientry rubber stopper or a controlled diameter injec-tion-molded insert, useful where multiple administration of a drug is required. Viscous products, with apparent viscosities of less than 15,000 centipoise, and suspension products can be handled by B/F/S machines with specially designed product fill systems. These types of products use innovative liquid-handling systems to maintain multiple-component products in a homogeneous solution during the filling process. Basically, if the solution will flow and if it can tolerate a minimum residence time, it can be packaged in an advanced aseptic B/F/S machine.

The latest advanced models of aseptic B/F/S systems are capable of manufacturing containers ranging in size from 0.2 mL to 1,000 mL at production rates of up to 15,000units per hour. Pharmaceutical companies that use such technological advances in aseptic B/F/S equipment design and systems will realize the highest level of quality in theproduction of their sterile liquid products. The ability to provide these B/F/S systems, which must meet corporate, scientific, regulatory and end-user requirements, can be aquite demanding. These application challenges are being met, however, by continuously evolving and improving B/F/S system and container designs, driven by the need forenhanced product integrity and patient safety.


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About Weiler Engineering:Weiler Engineering is a worldwide provider of aseptic Blow/Fill/Seal custom packaging machinery for pharmaceutical and healthcare applications. Based in Elgin, Illinois, andfounded in 1959, Weiler’s proprietary Blow/Fill/Seal system is the culmination of 40 years of innovation in machine de-sign and sterile process development, producing a highlyadvanced aseptic liquid packaging system. Its ASEP-TECH® Blow/Fill/Seal technology integrates blow molding, sterile filling and hermetic sealing in one continuous opera-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

and end-user requirements. These application challenges are met through the offering of several machine models designed to manufacture containers ranging in size from 0.1 mL to 1,000 mL at production rates of up to 15,000 units per hour, depending on container configuration.

To reach Weiler Engineering, please contact Chuck Reed; 1395 Gateway Drive, Elgin, Illinois 60124; Phone 847-697-4900; email [email protected];www.weilerengineering.com


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Aseptic Blow/Fill/Seal: A Sustainable Process for Packaging Pharmaceutical Liquids

Sustainability is increasing in importance in all internation-al markets. The pharmaceutical industry is no exception, considering its environmentally taxing processes involv-ing solvents, reagents, water and other agents. Along with sterility assurance, process validation and regulatory compliance, sustainability is becoming a more high-profile component in pharmaceutical processing, and is consid-ered a critical factor in the design of healthcare equip-ment, products and packaging.

The concept of sustainability has been a topic of interest for many years, and has been more formally discussed and considered since the late 1980’s. Current international focus has led to the development of regulatory guidance in many of the world’s markets.

The United States Environmental Protection Agency has posted the following definition of sustainability on its web-site www.epa.gov/sustainability/basicinfo.htm: “Sustainabil-ity is based on a simple principle: Everything that we need

for our survival and well-being depends, either directly or indirectly, on our natural environment. Sustainability cre-ates and maintains the conditions under which humans and nature can exist in productive harmony, that permit fulfilling the social, economic and other requirements of present and future generations.”

The major emphasis with sustainable procedures in phar-maceutical manufacturing is directed to the reduction of environmental impact, by decreasing consumption of raw materials and energy usage in manufacturing and pack-aging processes, and by increasing the utilization of more recycled materials.

There are many processes in pharmaceutical manufactur-ing that can be addressed to improve sustainability, and at the same time reduce operating costs. One of the most critically important objectives in achieving sustainability is reduc-ing process energy consumption.

Aseptic Blow/Fill/Seal systems for packaging pharmaceutical liquids incorporate materials and process that provide critical advantages for sustainable initiatives.


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Implementing energy-efficient practices and technologies should be a senior priority at the component, process and system levels.

Energy monitoring systems and process control systems are key tools that play an important role in energy manage-ment to reduce energy use. Such systems include meter-ing, monitoring, and system controls such as integrated programmable logic controllers (PLCs). These minimize the time required to perform complex tasks and increase efficiency in process operations. Such automated process technologies that reduce energy consumption can also improve product quality and consistency, and increase pro-duction throughput.

Embracing process sustainability and energy efficien-cy in the pharmaceutical industry is the aseptic Blow/Fill/Seal (B/F/S) system for packaging pharmaceutical liquids, which has made significant strides in achieving sustainability objectives.Aseptic B/F/S technology integrates the three-step process of blow molding, sterile filling and hermetic sealing in one continuous, highly-automated operation. Unique to aseptic B/F/S systems compared to traditional aseptic processing is their capability for rapid container closure and minimized aseptic interventions.

B/F/S is a self-contained process, where the raw materials are virtually completely recyclable. The consolidation of process steps through the use of B/F/S results in a signifi-cant reduction in the carbon footprint for the entire liquid filling and packaging production process. The products produced by aseptic B/F/S present a strong platform for sustainability from a variety of perspectives.

Assessing Sustainability in Pharmaceutical Manufacturing Pharmaceutical manufacturers possess a wide degree of latitude in selecting and implementing systems for achiev-ing environmental sustainability and energy efficiency. But foremost is the necessity to have a structured methodology that clearly delineates overall sustainability initiatives and process improvements.

Two basic types of structured programs are available to companies that manufacture pharmaceutical products: a) programs that address multiple aspects of sustainability, such as LEED (Leadership in Energy and Environmental De-sign), which provides a step-by-step process to achieve cer-tification and recognition of having reached specific levels of compliance; and, b) programs that provide assessment and planning tools for reducing energy consumption and plant

CONTINUED Aseptic Blow/Fill/Seal: A Sustainable Process for Packaging Pharmaceutical Liquids

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process costs. Both types of programs use a set of guide-lines for evaluating the environmental impact involved when manufacturing, packaging and distributing a product.

LEED is a certification program developed by the U.S. Green Building Council (USGBC) that can be applied to any building type and any building life cycle phase. It provides a framework for identifying and implementing practical and measurable green building design, construction, operations and maintenance solutions.

LEED promotes a whole-building approach to sustainabil-ity by recognizing performance in key areas, such as sus-tainable sites, water efficiency, energy, materials, indoor environmental quality, location and building design. The program’s internationally recognized green building cer-tification system provides third-party verification that a building was designed and built using strategies aimed at improving performance across these metrics. Although LEED certification does cover the actual phys-ical facility and its habitable spaces, it does not provide benchmarks for manufacturing and packaging processes within the plant. For pharmaceutical manufacturers, whose plant operations represent a significant energy draw which sizably impacts their sustainability, a more process-orient-

ed sustainability program would be needed to accurately assess environmental impact.

Similar to LEED is Green Globes, operated by the Green Building Initiative in the United States. Green Globes is a building environmental design and management tool used throughout the United States and Canada. It encompasses both sustainability and energy management criteria, such as integration of energy efficient systems, renewable en-ergy, cogeneration and on-site wastewater treatment sys-tems, in additional to sustainable environmental practices such as sustainable site development and indoor air quality.

Green Globes delivers an online assessment protocol, rating system and guidance for green building design, operation and management for light industrial applications like pharmaceutical manufacturing. But the program does not govern industrial process – which omits the significant energy savings that can be achieved when taking these processes into account.

The Building Research Establishment’s Environmental As-sessment Method (BREEAM) is a leading European envi-ronmental program for building practices in sustainable design. The program can assess light industrial operations like


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pharmaceutical plants, such as manufacturing, assembly and packaging facilities both at the design stage and after construction. Factors considered are energy management, wastewater, land use, pollution, building materials, and other sustainability factors. Credits are awarded in each of the above areas according to performance. A set of envi-ronmental weightings then enables the credits to be added together to produce a single overall score.

But like LEED and Green Globes, process assessment is not covered in this program, which means it is an incomplete assessment system for the sustainability requirements of pharmaceutical manufacturers.

A program that does address process in pharmaceutical plants is Energy Star, sponsored by the U.S. Department of Energy (DOE), and administered through the Environmental Protection Agency. Its program provides tools and resourc-es to help improve the energy efficiency of manufacturing and industrial facilities, including plant manufacturing and packaging processes.

Energy Star supplies an energy guide specifically for the pharmaceutical industry, which helps manufacturers evalu-ate potential energy improvement options, and develop ac-tion plans and checklists for the energy program. A major

benefit is that it allows industrial companies to measure the energy use of their facility, and to benchmark it with other, similar facilities. Companies input key plant operating data into an energy performance indicator to receive an effi-ciency score. It is a critical management tool for evaluating how efficiently a plant is using energy compared to other companies in their industry.

Also supporting energy efficiency in pharmaceutical pro-cesses is the DOE’s Industrial Technologies Program (ITP), run by the Office of Energy Efficiency and Renewable Energy. This program addresses process functions in man-ufacturing plants that utilize steam, compressed air, process heat, electric, and other systems that could potentially be a source of wasted energy. It focuses on the reduction of energy usage by integrating new technologies in industrial controls, automation and robotics, and provides concrete guidelines to achieve energy sustainability.

The ITP regularly conducts and makes available analytic studies to identify energy-reduction opportunities with-in industrial processes, making these results available to participant manufacturers. Application of the ITP program has resulted in significant energy savings, waste reduction, increased productivity, lowered emissions and improved product


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quality for U.S. industrial manufacturers.

Choosing the right program is critical to how quickly a pharmaceutical manufacturer’s energy efficiency and sus-tainability goals can be achieved. A company’s best strat-egy may be to utilize more than one of these programs. A plant may decide to run with Energy Star or ITP for its process energy improvements, while simultaneously going with LEED or Green Globes for its other sustainability ini-tiatives. Or, a manufacturer may choose to integrate state energy efficiency programs with LEED, Green Globes or ITP to capitalize on state energy credits or low interest loans and grants that the states may offer for energy-efficient solutions or equipment.

Life Cycle Analysis and B/F/S The environmental performance of products and processes in all industrial sectors, including pharmaceutical processing, has become a key issue. To better determine how sustain-able products and processes really are, life cycle analysis (LCA) has emerged as a recognized instrument to assess the ecological burdens and impacts connected with them.

A life cycle analysis is unique as a technique because it as-sesses environmental impacts associated with all stages of a product’s life from cradle to grave. This includes from raw

material extraction through materials processing, manufac-ture, distribution, use, repair and maintenance, and dispos-al or recycling. LCA can be used to find the most ecolog-ical way to improve product manufacturing, and can be a useful decision-making tool for new products and process development. It can also be used as a guide for the opti-mization of energy and raw material consumption.

Cradle-to-grave life cycle analysis, through mathematical modeling, makes it possible to determine and manipulate key metrics to provide a weighted average on total sustain-ability. Values for energy and resource consumption, the extraction and processing of the raw materials, the pollu-tion produced, recyclability and the effects of associated transportation on the environment are applied in a numeri-cal equation. The weighted average then gives a clear evaluation of a sustainable solution for the product and manufacturing/packaging process being examined. The LCA process is a systematic, phased approach and consists of four components: 1) establishing the context and parameters of the analysis; 2) an inventory, consisting of an identification and quantification of energy, water and materials usage and environmental releases; 3) an impact assessment of these inventory factors, and the potential human


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and ecological effects; and 4) the different environmental impacts are weighted relative to each other, then summed to get a single number representing the total environmen-tal impact.

An LCA allows a decision maker to study an entire product system and its processes, thereby avoiding the sub-opti-mization that could result if only a single process were the focus of the study.

In a comparison of different liquid pharmaceutical contain-ers, for example, to determine which container had the lowest releases to the environment and least affected the supply of natural resources, an LCA would quantify the raw materials used and the environmental loadings (including energy consumption) from the manufacturing and packag-ing processes used to produce each container. Also viewed would be comparative ecological impacts from distribution, consumption and disposal or reuse of each container.

When selecting between two packaging processes, for ex-ample, it may appear that one is better for the environment because it generates less chemical emissions at the point of packaging. However, after performing an LCA, it could be determined that the preferred process actually creates larg-er cradle-to-grave environmental impacts when measured

across its influence on air, water and land. The packaging process may use a film that is difficult or impossible to recy-cle. Therefore, the unselected process may now be viewed as producing less cradle-to-grave environmental harm or impact than the initial preferred technology.

From a life cycle analysis perspective, aseptic Blow/Fill/Seal machines that provide packaging of pharmaceutical liquids present much more streamlined and sustainable systems for production of sterile products, compared to traditional aseptic processing in a number of critical aspects:

Energy Management – The most advanced aseptic B/F/S systems are quite automated, compared to traditional aseptic processing. These B/F/S machines are designed to require minimum human access while operating in Class-100 environments.

Various in-process control parameters utilizing the latest generation of fully system-integrated PLCs, control and monitor container weight, fill weight, wall thickness, iso-lation of visual defects and other factors, facilitating opti-mized system function.

These B/F/S machines allow very efficient processing speed and


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short machine cycle times. Aside from the obvious im-provement in throughput volume, they provide more effi-cient energy usage.

According to the DOE’s Energy Star program, implementa-tion of monitoring and control systems, such as PLCs and servo-drives, present well-documented opportunities for energy savings.

Recyclable Plastic Containers – Aseptic B/F/S systems in-corporate the use of recyclable plastic resins, as differentiat-ed from glass containers used in traditional aseptic process-ing. Low-density polyethylene, high-density polyethylene and polypropylene, used to produce aseptic containers for injectables, ophthalmics, biologicals and vaccines are gen-erally considered inert by the FDA. These inert materials do not contain additives, have low water vapor permeabil-ity, and are easy and safe to handle in critical care environ-ments such as hospitals.

These resins used in B/F/S processes are recyclable. Reg-ulatory requirements permit reuse of the resin up to three times before it must be discarded. As much as 50 percent of the resin used in the B/F/S process can be reground and directly used again within the process when mixed with vir-gin material. The remainder of the waste can be captured

and used for other applications. The entire production and recycle processes can be maintained on-site with minimal need for off-site disposal of waste material.

Reduced Manual Interventions – Waste reduction should be viewed as an important objective in a sustainability program. In aseptic packaging of pharmaceutical liquids, waste can manifest itself in compromised quality, labor-in-tensive processes and reduced efficiency.

Traditional aseptic procedures for packaging pharmaceu-tical liquids involves multiple steps in the handling and manipulation of the material, containers and sterilization filling processes with human intervention, and therefore have a higher potential for contamination during process-ing. Additional processing steps for conventional aseptic processing include receiving, inspection and warehousing of incoming containers, washing and sterilizing of contain-ers, separate processing steps and equipment for filling and sealing, and end processing handling such as labeling. The FDA’s 2004 Guidance for Industry Sterile Drug Products Produced by Aseptic Processing states that the design of equipment used in aseptic processing should limit the num-ber and complexity of aseptic interventions by personnel.


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Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product, container-closures or the surrounding environment.

The latest generation of Blow/Fill/Seal machines, as ex-emplified in the ASEP-TECH® B/F/S system from Weiler Engineering, are highly automated, thereby severely reduc-ing manual interventions. The forming, filling and sealing steps are achieved in one unit operation – the cycle being completed within seconds. Such automation eliminates unneeded manpower and reduces the risk to lessened product integrity.

Elimination of Secondary Packaging – B/F/S produced vi-als and bottles, by virtue of their opening features and sim-plified designs, such as twist-off tops, eliminate the need for secondary packaging. Labeling is not needed, since the molds can be engraved with product information. This avoids an additional process step, and eliminates material usage and the potential for additional waste generation.

Integrated Packaging of Inserts – B/F/S allows pre-mold-ed, pre-sterilized components, called inserts, to be inte-grated 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 cal-ibrated drop, are attached to the container after the blow-ing and filling process. These improvements streamline the packaging process.

Changeover Flexibility – When aseptic throughput is in-terrupted, or not running because of downtime, the entire process line is affected, which represents a significant pro-duction loss to the manufacturer. Many B/F/S machines are configured to produce more than one bottle shape or for-mat. This makes it easy to change over from one container size to another. A Blow/Fill/Seal machine might produce a family of 2, 3 and 5ml, then switch to a family of 5, 10 and 15ml, or to one of 10, 15 and 20ml, moving from one to the other with relative ease of machine set-up.

B/F/S systems approach 99 percent uptime efficiency, sig-nificantly higher than traditional aseptic processing, which is plagued with slow-downs and process interruptions in part because of required manual interventions.

Embracing Sustainability The Blow/Fill/Seal system improves product integrity and better ensures patient safety over traditional aseptic pro-cessing procedures. As a result, the United States Food and Drug


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Administration and the United States Pharmacopoeia now characterize modern B/F/S technology as an “advanced aseptic process”, indicating its use as a preferred technolo-gy over other aseptic systems, and a better solution for the sterile, aseptic processing of pharmaceutical liquids.

Waste reduction, resource and energy management, im-proved process controls and throughput efficiency are key factors that have influenced the acceptance of aseptic Blow/Fill/Seal. These are critical functions for achieving sustainable practices in the packaging of aseptic pharma-ceutical liquids. They save energy, increase productivity, and reduce environmental impacts.

Advanced aseptic Blow/Fill/Seal technology has emerged as an innovation in green technology within the pharma-ceutical packaging sector. As government agencies and pharmaceutical manufacturers steadily, but surely, embrace the sustainability initiative, aseptic Blow/Fill/Seal technol-ogy will continue to occupy a prominent position in the evolution of “Green Processing”.

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,

and founded in 1959, Weiler’s proprietary Blow/Fill/Seal system is the culmination of 40 years of innovation in ma-chine design and sterile process development, producing a highly advanced aseptic liquid packaging system. Its ASEP-TECH® Blow/Fill/Seal technology integrates blow molding, sterile filling and hermetic sealing in one continuous opera-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 and end-user requirements. These application challenges are met through the offering of several machine models de-signed to manufacture containers ranging in size from 0.1 mL to 1,000 mL at production rates of up to 15,000 units per hour, depending on container configuration.

To reach Weiler Engineering, please contact Chuck Reed; 1395 Gateway Drive, Elgin, Illinois 60124; Phone 847-697-4900; email [email protected]; www.weilerengineering.com


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Improving Process Quality of PharmaceuticalLiquids – Aseptic Blow/Fill/Seal Technologyvs. Traditional Aseptic Processing

Since its introduction into the North American phar-maceutical market more than 40 years ago, blow/fill/seal (B/F/S) aseptic processing has established itself as a highly efficient and safe system for the filling and packaging of sterile pharmaceutical liquids and other healthcare products, such as creams and ointments. B/F/S product usage has been widely established in the ophthalmic and respiratory therapy markets for some time, and lately B/F/S technology has been gain-ing increasing worldwide acceptance in the parenteral drug marketplace, replacing traditional glass vial pro-cessing in a growing number of applications. B/F/S enables a container to be molded from plastic, aseptically filled and hermetically sealed in one con-tinuous, integrated and automatic operation, without

human manipulation. The process provides flexibility in container design and system changeovers, high vol-ume product output, low operational costs and a high assurance of product sterility. The inherent safety of the process – packaging sterile products under aseptic conditions without human intervention – has led the FDA, and the United States Pharmacopoeia, to char-acterize B/F/S technology as an “advanced aseptic process”, indicating its use as a preferred technology.

New advances in drug delivery, the desire to improve convenience in handling pharmaceutical products, growing emphasis on combination products, the increasing focus on pro-tein-based drugs and other bi-ologics, and tighter regulatory

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.


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criteria on product safety, have focused more attention on B/F/S technology over traditional aseptic methods as a better solution for the sterile, aseptic processing of pharmaceutical liquids.

Traditional Aseptic Processing and Sterility of Pharmaceutical Liquids Microbial contamination is a serious issue for com-panies manufacturing liquid pharmaceutical formula-tions. Such liquids are ideal growth areas for bacteria like Salmonella, E. coli and Staphylococcus, microbes that have been found in various liquid drug products. A supposedly sterile, but contaminated product may result in deterioration of the drug and loss of potency, pyrogenic reactions after administration to a patient – particularly in parenterals, infection of the patient and colonization of microorganisms in the patient with the risk of a secondary infection. Any microorganism, pathogen or nonpathogenic, found in a supposedly sterile pharmaceutical product is dangerous.

Drug manufacturers have pursued various methods of sterilizing packaging components, product ingredients and equipment in order to achieve a sterile product in

its final form. One system used is traditional process-ing, followed by terminal sterilization, which involves initially filling and sealing product containers within a cleanroom environment. The environment is set up to minimize the microbial content of the product while it is being manufactured. Each component of the pro-cess – the product, container and closure – have a low bioburden, but may or may not be sterile. The prod-uct, in the final container, is subjected to a “terminal” sterilization process, such as heat or radiation. The most common method uses autoclaving with saturated steam under pressure.

Traditional aseptic processing allows a final sterile drug product to be achieved by individually sterilizing the containers, material and equipment in-process, result-ing in a unified sterilized product. In traditional aseptic processing, the containers are either supplied cleaned and sterilized to the filling line, or they are cleaned and sterilized within the aseptic filling line. Plastic contain-ers are usually washed, dried, sterilized and cooled be-fore filling. Glassware containers, which have been the dominating packaging materi-al for terminally sterilized and

CONTINUED Improving Process Quality of Pharmaceutical Liquids – Aseptic Blow/Fill/Seal Technology vs. Traditional Aseptic Processing

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traditionally sterilized pharmaceutical liquids, are usu-ally sterilized in-line, exposed to hot air at 350 degrees C while being passed through a Class 100 tunnel. A glass container temperature of 180 to 200 degrees C is adequate for achieving sterility.

Methods of sterilization used in aseptic processing in-clude filtering the solution by dissolving it in a solvent, such as Water For Injection (WFI), where the solution is passed through a sterilizing filter or membrane. Filter sterilization is used where the component is soluble and likely to be adversely affected by heat. A variation of this method includes subjecting the filtered solution to aseptic crystallization and precipitation (Lyophiliza-tion) of the component as a sterile powder. Dry heat sterilization is another effective method for sterilizing components that are heat stable and insoluble. Irradi-ation can also be used to sterilize some components. Aseptic processing handles components, materials and equipment in such a manner that foreign microbial and endotoxin contaminents that exceed pre-determined acceptable levels, are not introduced to the product stream. To this end, it is critical that all storage, con-

veying, filling and container sealing stages be careful-ly controlled at each step of the process to maintain sterility of the product. Traditional aseptic processing, involving filling open glass bottles or vials, requires that the manufacturer maintain aseptic conditions in critical processing areas at all times. Unfortunately, the majority of liquid drug product contamination over the past several decades has come about from products produced in traditional aseptic processing facilities.

Personnel Intervention inTraditional Aseptic Critical Areas Traditional aseptic sterilization involves handling and manipulation of the material, containers, and steril-ization filling processes with human intervention, and therefore has a higher potential for contamination during processing. The FDA’s 2004 Guidance for In-dustry Sterile Drug Products Produced by Aseptic Processing states that the design of equipment used in aseptic processing should limit the number and com-plexity of aseptic interventions by personnel. Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the poten-

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tial for introducing contaminants to exposed product, container-closures or the surrounding environment.

Ordinary walking by a person emits roughly 10,000 skin particles per minute. Such particles can and do hold microbial contamination. A rip in a worker’s uniform, a momentary exposed wrist, a mask placed too low on the nose or physical contact with an open fill port will increase microbial contamination within a critical area.

According to the FDA’s guide, airborne contamination is directly related to the number of people working in a cleanroom and the level of congregation by personnel in areas where critical aseptic manipulations are per-formed. Isolation of personnel from these critical areas would eliminate the major source of contamination in traditional aseptic processing.

In traditional aseptic processing, changing or adjusting filling nozzles and heads necessitates the shutdown of the filling operation and requires re-sterilization of the entire equipment. This increases manual intervention in this critical area. Cleaning and sterilization which is carried out by personnel, opens the door to breaching

of established procedures for microbial decontamina-tion and potential introduction of other particulates like dirt, oil and chemicals.

Mold is common flora found on floors, walls and ceil-ings of buildings. Contamination occurs due to the retention of water in cracks, edges and joints that are susceptible because of inadequate sealing. Brooms, mops and anything used for cleaning can become contaminated and increase atmospheric contamination because of raised dust or splashing water. In tradition-al aseptic processing, significant manual intervention is required in critical areas to maintain compliance with established sterile mandates.

Advanced Blow/Fill/Seal Aseptic Technology In advanced aseptic B/F/S processing, containers are formed from a thermoplastic granulate, filled with a liquid pharmaceutical product and then sealed within a continuous, integrated and automatic operation with-out human intervention.

Bulk solution prepared under low bioburden or sterile con-



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ditions is delivered to the machine through a product delivery system that has been previously sterilized using an automated steam-in-place process.

Modern B/F/S machines are fully automated, designed to require minimum human access and operate in a classified environment using the following steps: (a) granules of a polymer resin, conforming to a predeter-mined set of specifications, such as polyethylene, poly-propylene, co-polymers or other blow-moldable resins, are pneumatically conveyed from a non-classified area into the hopper of the B/F/S machine, from which the plastic is fed into a multi-zone rotating screw extruder which produces a sterile homogenous polymer melt (160–250 degrees C); (b) then to a parison head which produces hollow tubular forms of the hot resin (called parisons). The parisons are prevented from collapsing by a stream of sterile filtered support air. Some high-speed B/F/S machines have up to sixteen parisons be-ing formed simultaneously; (c) container mold(s) close around the parisons, and the bottom of the parison is pinched closed, while the top is held open in a molten state; (d) the container is formed in the mold by blow-ing sterile air or creating a vacuum; (e) filling needles

deposit the stipulated volume of product into the container; (f) the filling needles are withdrawn, and the upper part of the mold closes to form and seal the up-per part of the B/F/S container; (g) the mold is opened and the completed, filled containers are conveyed out of the B/F/S machine to a remote station where excess plastic is removed and the finished product is then conveyed to final packaging.

Various in-process control parameters, such as contain-er weight, fill weight, wall thickness and visual defects provide information that is monitored and facilitates ongoing process control.

The forming, filling and sealing steps are achieved in one unit operation – the cycle being completed within seconds. Automation of B/F/S process steps eliminates manual intervention and reduces risk to the product. No production personnel are present in the filling room during normal operation.



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Microbial and Particulate Integrity in the Aseptic Blow/Fill/Seal System Sterility of B/F/S polymeric containers, materials and processes is validated by verifying that time and tem-perature conditions of the extrusion, filling and sealing processes are effective against endotoxins and spores.

Challenge studies have been conducted on the ste-rility levels of advanced B/F/S technology, which demonstrate a uniform capability of achieving contamination rates not exceeding 0.001 percent throughout the entire process. Even higher sterility assurance levels, approaching 0.000001 percent, have been achieved using high levels of airborne microbio-logical challenge particles.

Endotoxins are a potential pyrogenic contaminant, es-sentially dead bacterial cellular matter. They can lead to serious reactions in patients, particularly with those receiving injections, ranging from fever to death. A critical aspect of B/F/S technology is its pyrogen-free molding of containers and ampoules. Extensive exper-iments confirming the efficacy of the B/F/S extrusion process have been performed using high levels of

spores and endotoxin-contaminated polymer granules. The typical B/F/S extruders have demonstrated spore contamination rates of 0.000001 percent, and 0.00001 percent for endotoxins.

Control of air quality is critical for sterile drug prod-uct manufacture. B/F/S equipment design typically employs the use of specialized measures to reduce microbial contamination and particle levels that can contaminate the exposed product. The B/F/S pro-cess inherently produces a very low level of particulate matter and much of potential B/F/S microbial contam-ination (viable) in the air is mitigated by the absence of manual intervention in its critical areas. Non-viable particles generated during the plastic extrusion, cut-ting, and sealing processes are controlled. Provisions for carefully controlled airflow protect the product by forcing created particles outward while preventing any inflow from the adjacent environment. These “zones of protection” can also incorporate designs that sepa-rate them from the surrounding environment, provid-ing additional product protection.



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The B/F/S critical processing zone is continually sup-plied with HEPA-filtered air by an air shower device (shroud). The B/F/S critical zone is the area where the containers are exposed during filling. Air in the critical zone meets Class 100 (ISO 5) microbiological standards during operations. The critical zone is con-tinuously monitored to ensure a positive differential pressure is maintained between the shroud and the adjacent cleanroom.

Plastic vs. Glass Containers Injectables, ophthalmics, biologicals and vaccines are produced in a number of different types of containers, including bottles, vials and ampoules that are made from glass and plastic. Protecting the contents of these aseptic liquid drugs through filling, packaging and transportation, and allowing for safe and easy administration are critical objectives in the aseptic process. The industry is infused with a strong quality control emphasis. Raw materials, and in-process and finished products are continually checked for approval and rejection.

The packaging needs for pharmaceutical liquids are

quite demanding. It is not unusual for degradation of the product to occur during processing or while in transit. The physical properties of liquids can be al-tered with inadequate packaging components. For aseptic filling, the package must be produced, stored, filled and sealed under conditions that preserve steril-ity. Likewise, the appearance of particulates in sterile solutions is equally undesirable.

Glass, although a standard in the aseptic pharmaceuti-cal liquids industry, is not without its limitations. There is the safety issue – glass vials are subject to breakage, both in transit and while being administered. Handling glass containers always involves a certain amount of risk of lacerations and glass splinters. Glass ampoules, for example, generate a fine array of small glass parti-cles during opening.

Manufacturers using glass containers are also subject-ed to design limitations when the designs become somewhat complex. With glass containers, as design complexity increases so does the cost. Once glass containers are produced, they need to be transported



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to the aseptic facility. Glass is typically transported in cardboard boxes that can contain mold spores, such as Penicillin sp. and Aspergillus sp., as well as bacteria like Bacillus sp. Paper, also used in the shipping of glass, can also contain mold spores. The rubber closures used on the glass containers can have mold contamination.

Domestic drug companies have been slow to change to plastic, primarily due to the existing installed base of glass production of small-volume parenteral drugs in the United States. However, the same is not the case with new drugs that are coming onto the mar-ket. These are more frequently being looked at, and submitted for FDA approval, in plastic containers pro-duced by advanced B/F/S aseptic processing. Sup-porting this move is that the B/F/S processing resins, polyethylene and polypropylene, are generally con-sidered inert by the FDA. Many of the blow molding resins used in B/F/S processing have received interna-tional acceptance as suitable for food and drug ap-plications, and many of the drug products produced outside of the United States can be found packaged with these resins.With the continued refinement of BSF technology, its

acknowledgment by the FDA as a preferred technolo-gy for aseptic processing, and its growing acceptance by drug companies, the migration from glass to plastic containers used for aseptic pharmaceutical liquids is growing rapidly. It has become more cost effective to use plastic containers for aseptic liquids, which effectively costs manufacturers one-third of the cost of glass. Plastic is less expensive to ship because the containers are lighter. For small-volume parenterals, the use of plastic is inevitable, and increasingly being considered for these reasons.

Although many B/F/S systems make available only a lim-ited number of container choices within each container category, some B/F/S machines do allow for broad ver-satility in container design. Advanced B/F/S machines can design virtually any container mold through the use of sophisticated CAD/CAM technology and 3-D mod-eling. These design systems, when interfaced with the latest in CNC and EDM machinery, ensure fabrication of key components to precise tolerances.

B/F/S machine designs also allow for mounting of sepa-



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rate sterile items (inserts) within the B/F/S container, and in-mold coding and engraving, which provide further opportunities for innovative design over that of glass products.

Flexibility with Changeovers Allows Shorter Runs, Increased Uptime, Maximized ThroughputModern B/F/S system design is focused on simplicity and flexibility. Many B/F/S machines are configured to produce more than one bottle shape or format. This makes it easy to change over from one container size to another. A B/F/S machine might produce a family of 2, 3 and 5ml, then switch to a family of 5, 10 and 15ml, or to one of 10, 15 and 20ml, moving from one to the other with relative ease of machine set-up. This is ideal for manufacturers performing contract packaging of aseptic liquid pharmaceutical solutions, because of their need for changeover flexibility.

The growing usage of biologics is demanding packaging in different formats. They usually require smaller process runs and are typically heat sensitive. Many of these new biotechnological drugs do not withstand steam steril-ization or irradiation and so are best treated aseptically.

More advanced B/F/S machines have been designed so they can handle these heat sensitive products.

Machine models are available that can produce con-tainers ranging in size from 0.1mL to 1000mL at pro-duction rates of 15,000 units per hour, depending on container configuration.

B/F/S machine efficiency is very high. More advanced B/F/S machines can approach 99 percent uptime ef-ficiency, which is significantly higher than traditional aseptic processing which is plagued with slow-downs in part because of manual interventions. To further minimize potentials of system downtime, some manu-facturers are now segmenting their high-volume pro-cess lines into more short-run lines, in the event that if one of the lines goes down for maintenance or repair, it will not stop the entire production throughput.

When aseptic throughput is interrupted, or not running because of downtime, the entire process line is affect-ed, which represents a significant production loss to the manufacturer.



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An Aseptic Technology Destined to Prevail More rapid container closure processing, elimination of aseptic critical-area personnel interventions, in-creased system uptime over traditional processing, pyrogen-free molding of containers and ampoules, more flexibility with container design, and an increased capability to capitalize on short runs – these are some of the benefits for manufacturers inherent in advanced blow/fill/seal aseptic technology. And for consumers, increased safety and confidence in their drug products. These are advances that are significant, if not fully real-ized yet within the aseptic liquid pharmaceutical mar-ketplace. But it is apparent that advanced B/F/S asep-tic technology is destined to become a major player in this arena.

About Weiler Engineering: Weiler Engineering is a worldwide provider of aseptic blow/fill/seal custom packaging machinery for pharma-ceutical and healthcare applications. Based in Elgin, 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-

velopment, producing a highly advanced aseptic liq-uid packaging system. Its ASEP-TECH® blow/fill/seal technology integrates blow molding, sterile filling and hermetic sealing in one continuous operation to pro-duce aseptically manufactured products.

The company uses the latest technological advanc-es in equipment design and systems to ensure the highest level of quality in the production of sterile liquid products. Its equipment must meet demanding corporate, scientific, regulatory and end-user require-ments. These application challenges are met through the offering of several machine models designed to manufacture containers ranging in size from 0.1mL to 1000mL at production rates of up to 15,000 units per hour, depending on container configuration.







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Improving Uptime in Aseptic Processing of Pharmaceutical Liquids with Blow/Fill/Seal

Pharmaceutical manufacturers, for many years, have expe-rienced exceptional growth with the development of new drugs and the marketing of these products, but pharmaceuti-cal manufacturing processes have historically lagged behind in efficiency compared to those of other consumer product industries. Within the past decade, however, responding to changes in consumer purchasing such as the influence of the Internet, stiffer guidelines from the Food and Drug Adminis-tration and other regulatory agencies, and significantly in-creased costs to bring new drugs to market, drug companies have had to take a closer look at their manufacturing process-es to make them more efficient, to stay competitive.

A key factor to reaching high levels of efficiency in phar-maceutical manufacturing is maintaining uptime, which has always been of critical importance to manufacturers in every industry. When throughput is interrupted, or not running because of downtime or changeovers, the entire process line is affected, which can present a significant production loss to the pharmaceutical manufacturer.

Overall Equipment Effectiveness An important tool that pharmaceutical manufacturers are using to increase uptime, and measure and improve line efficiency is Overall Equipment Effectiveness (OEE). OEE measurement is also frequently used as a key performance indicator (KPI) in conjunction with lean manufacturing ef-forts to provide an indicator of success.

Overall Equipment Effectiveness (OEE) is a system of ana-lytics to determine how effectively a manufacturing opera-tion is utilized. It identifies and quantifies the performance of specific areas of a manufacturing line to bring about pro-cess improvement. OEE is determined by factoring three key metrics of machine and line operation: 1) availability; 2) performance; and 3) product quality.

Availability represents the per-centage of scheduled time that the process is available to op-

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.


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erate. Also referred to as uptime. Factors like equipment cleaning, changeovers, equipment breakdown and preven-tative maintenance are conditions that will influence the OEE metric rating for Availability.

Performance represents the speed at which the process or machine runs as a percentage of its designed speed. Fac-tors that influence the OEE rating for Performance include temporary equipment stops from jams, machine cycle set-tings, designated speed and product throughput.

Quality in the OEE metric represents the good products produced as a percentage of the total units started. This OEE rating is influenced by rejected products. More specif-ically, those rejects caused by equipment or personnel, and those rejects separated into rework and scrap.

Each of these metrics are then factored at a percentage of operation compared to the ideal operating condition. For example, a given line may have an Availability factor of 86.7 percent, a Performance rating of 93.0 percent, and a Quali-ty factor of 95.0 percent. The OEE would then be comput-ed by multiplying 86.7% x 93.0% x 95.0%, for a composite OEE metric of 76.6 percent for that line.

Typically, each metric would factor in many pieces of equip-

ment and operating aspects of the pharmaceutical line to arrive at a percentage. In pharmaceutical packaging these machines may include sorters, fillers, cappers, label-ers, cartoners, case packers and palletizers. Each machine would have its own systems and cycles. An OEE rating can be determined for each machine on the line, and/or for the entire line.

Blow/Fill/Seal Processing of Aseptic Pharmaceutical Liquids One area of pharmaceutical manufacturing that has made significant gains in Overall Equipment Effectiveness is in the packaging of aseptic pharmaceutical liquids with Blow/Fill/Seal (B/F/S) technology. From the perspective of OEE, and focusing on uptime and changeover time improvement, aseptic Blow/Fill/Seal machines present highly efficient sys-tems for production of sterile liquid products.

The aseptic Blow/Fill/Seal system has proven to improve product integrity and better ensure patient safety over traditional aseptic processing procedure. As a result, the United States Food and Drug Administration and the Unit-ed States Pharmacopoeia now characterize modern B/F/S technology as an ‘advanced aseptic process’, indicating its use as a preferred technology over other aseptic systems, and

CONTINUED Improving Uptime in Aseptic Processing of Pharmaceutical Liquids with Blow/Fill/Seal

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a better solution for the sterile, aseptic processing of phar-maceutical liquids.

B/F/S is a self-contained process. The consolidation of pro-cess steps results in streamlined efficiency for the entire liq-uid filling and packaging production process. The technol-ogy integrates a three-step process of blow molding, sterile filling and hermetic sealing in a continuous, highly-automat-ed operation. Unique to aseptic B/F/S systems compared to traditional aseptic processing is their capability for rapid container closure and minimized aseptic interventions. Fur-ther, B/F/S incorporates the use of recyclable plastic resins. Low-density polyethylene, high-density polyethylene and polypropylene, used to produce aseptic containers for in-jectables, ophthalmics, biologicals and vaccines are gener-ally considered inert by the FDA.

Simplified B/F/S Machine Design Improves Uptime Traditional aseptic procedures for packaging pharmaceuti-cal liquids involve multiple steps in the handling and ma-nipulation of the material, containers and sterilization filling processes with human intervention, and therefore have a heightened potential for system downtime and prod-uct contamination during processing. Manual processing steps for conventional aseptic processing include receiving, inspection and warehousing of incoming containers, wash-

ing and sterilizing of containers, separate processing steps and equipment for filling and sealing, and end processing handling such as labeling.

In pharmaceutical processing, it is the filling process that determines the line speed. System delays and downtime caused by such manually-dependent processes in aseptic packaging can have significant throughput and cost conse-quences which depress OEE.

Conversely, automating the aseptic process can have a sizable impact on improving uptime. The most advanced aseptic B/F/S systems are quite automated, compared to traditional aseptic processing. These B/F/S machines are designed to require minimum human access while operat-ing in Class-100 environments. Various in-process control parameters utilizing the latest generation of fully-system-in-tegrated PLCs, control and monitor container weight, fill weight, wall thickness, isolation of visual defects and other factors, facilitating optimized system function.

With the latest generation of Blow/Fill/Seal machines, as ex-emplified in the ASEP-TECH® B/F/S system from Weiler En-gineering, the forming, filling and sealing steps are achieved in one unit operation – the cycle being completed within seconds.


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Such automation eliminates unneeded manpower and re-duces the risk to product integrity. These B/F/S machines al-low very efficient processing speed and short machine cycle times. They minimize the time required to perform complex tasks and increase efficiency in process operations. Such au-tomated process technologies improve product quality and consistency, and increase production throughput, substan-tially supporting Overall Equipment Effectiveness.

Flexibility of B/F/S Container Design Optimizes Machine Operation B/F/S allows considerable flexibility in the design of con-tainers, adding to improved OEE. Pre-molded, pre-steril-ized components, called inserts, can be easily integrated into the basic container. These inserts, including items such as rubber and silicone stoppers, and tip-and-cap dropper units for eye drop containers used to deliver a calibrat-ed drop, are attached to the container after the blowing and filling process, prior to sealing. These improvements streamline the packaging process, eliminating the need for secondary packaging. Labeling is not needed, since the molds can be engraved with product information, which avoids an additional process step.

Advanced aseptic B/F/S containers and ampoules can be manufactured to deliver precise dosing in disposable for-

mats. The incorporation of a sterile tip-and-cap, a rubber stopper or a multi-entry insert into the B/F/S package offers added flexibility in container design and drug delivery methods, as well as enhanced sterility safety.

Quick Changeovers Packaging equipment changeovers present one of the most costly and time-consuming activities within pharmaceutical manufacturing. Indeed, changeover adaptability remains the most critical packaging machine feature, with sizable in-fluence on OEE. The versatility of packaging equipment to facilitate rapid changeovers has never been more important in pharmaceutical manufacturing, and aseptic Blow/Fill/Seal systems exemplify this initiative.

Many B/F/S machines are configured to produce more than one bottle shape or format. This makes it easy to change over from one container size to another. A B/F/S machine might produce a family of 2ml, 3ml and 5ml containers, then switch to a family of 5ml, 10ml and 15ml containers, or to one of 10ml, 15ml and 20ml containers, moving from one to the other with relative ease of machine set-up. This is ideal for manufacturers, such as those performing contract packaging of aseptic liquid pharmaceutical solu-tions, because of their need for changeover flexibility. ASEP-


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TECH® B/F/S systems from Weiler are capable of produc-ing containers ranging in size from 0.1ml to 1,000ml at production rates of 15,000 units per hour, depending on container configuration.

The growing usage of biologics is demanding packaging in different formats. These drug products usually require smaller process runs and are typically heat sensitive. Many of these new biotechnological drugs do not withstand ter-minal sterilization with steam or irradiation, and so are best treated aseptically. More advanced B/F/S machines are designed so they can handle these heat sensitive products without adversely affecting product quality.

The B/F/S process offers outstanding versatility for multi-ple container designs. A unique design feature offered on the ASEP-TECH® B/F/S systems, for example, permits the insertion of a secondary delivery device into the container prior to the final hermetic sealing step. This feature can be suspended, however, without requiring significant equip-ment changeover. This allows the production of standard containers without inserts on the same machine with only a simple recipe and tooling change.

To further minimize potentials of system downtime, some pharmaceutical manufacturers are now segmenting their

high-volume aseptic process lines into multiple, smaller Blow/Fill/Seal lines. The use of smaller machines provides enhanced production flexibility and improved efficiency. In the event that one of the lines goes down for maintenance or repair, it will not stop the entire production throughput. Products can be easily ‘campaigned’ with B/F/S, using one line with one container geometry for multiple products. Since B/F/S is ideally suited for these ‘campaigns’ due to quick changeovers, it is a natural pick for manufacturers desiring to optimize OEE.

Efficient Utilization of Time Modern B/F/S system design embodies OEE initiatives, being focused on changeover simplicity and flexibility, and permitting shorter runs, increased uptime and maximized throughput.

Blow/Fill/Seal machine efficiency rates very high. More advanced Blow/Fill/Seal machines can approach 99 per-cent uptime efficiency, significantly higher than traditional aseptic processing, which is plagued with slow-downs, in part because of manual interventions. B/F/S also performs noticeably higher than the peak 70 percent operating efficiency of the world’s most streamlined pharmaceutical manufacturing facilities.


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Improved uptime, minimized changeover time and efficient OEE are key factors that have influenced the acceptance of aseptic Blow/Fill/Seal. These are critical functions for achieving improved product quality and profitability in the packaging of aseptic pharmaceutical liquids.

About Weiler Engineering: Weiler Engineering is a worldwide provider of aseptic Blow/Fill/Seal custom packaging machinery for pharmaceutical and healthcare applications. Based in Elgin, Illinois, and founded in 1959, Weiler’s proprietary Blow/Fill/Seal system is the culmination of 40 years of innovation in machine design and sterile process development, producing a highly advanced aseptic liquid packaging system. Its ASEP-TECH® Blow/Fill/Seal technology integrates blow molding, sterile filling and hermetic sealing in one continuous opera-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 equipment must meet demanding corporate, scientific, regulatory and end-user requirements. These application challenges are met through the offering of several machine models designed to manufacture containers ranging in size from 0.1 ml to 1,000 ml at production rates of up to 15,000 units per hour, depending on container configuration.



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Streamlined Blow/Fill/Seal Insertion Technology Increases Flexibility and Safety in Aseptic Packaging of Pharmaceutical Liquids

The aseptic Blow/Fill/Seal (B/F/S) process has proven to be an ideal system for the creation of a wide vari-ety of container shapes and sizes used for packaging sterile pharmaceutical liquids. B/F/S is well suited to producing closed aseptic containers, like injectable products, that need to be opened under critically sterile conditions within a clinical environment such as a hospital, as well as sterile products opened by in-dividuals in work-a-day environments like ophthalmic dropper units. These products must meet the man-dates of drug manufacturers and government regula-tors that require sterile products that will stay sterile until the time of use. Manufacturers also desire the most cost-efficient packaging systems to achieve these ends without any loss of product integrity. One of the more recent improvements in aseptic B/F/S processing

that facilitates these goals is the advance in insertion technology. The latest generation of aseptic B/F/S machines incorporates dedicated isolators adapted specifically for insertion applications. These modular insertion isolators are typically located outside of the classified machine room, separate from but directly connected to the B/F/S unit through a transfer tunnel. The isolator and tunnel are typically sterilized with vaporized hydrogen peroxide and the Class 100 envi-ronment within it is maintained by HEPA filtration. This new addition to the aseptic B/F/S system has not only streamlined the insertion process, but has provided a higher level of sterility assurance for products with tip-and-caps and rubber/silicone stoppers inserted under asep-tic conditions.

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.

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

Unlike glass, plastic containers are shatter-proof. Glass vials are subject to breakage, both in transit and while being administered. Handling glass containers always involves a certain amount of risk of lacerations and glass splinters, such as with small volume parenterals, where glass ampoules can generate a fine array of small glass particles during opening.

A critical aspect of B/F/S technology is its pyro-gen-free molding of containers and ampoules. B/F/S processing resins, polyethylene and polypropylene, used to produce aseptic containers for injectables, ophthalmics, biologicals and vaccines are generally considered inert by the FDA, and many of the blow

molding resins used in B/F/S processing have received international acceptance as suitable for pharmaceuti-cal liquids applications. These inert materials do not contain additives, have low water vapor permeability, and are easy and safe to handle in critical care envi-ronments such as hospitals. Further, temperature-sen-sitive biological and protein-based products can be processed in advanced B/F/S machines, providing a level of enhanced sterility assurance.

For these reasons the interest in B/F/S-produced plas-tic containers, and particularly injectable product con-tainers, is continuing to grow within the pharmaceuti-cal industry.

Along with the growing interest in B/F/S plastic con-tainers, the application of aseptically-produced B/F/S containers with inserts has also become increasingly popular. Advanced B/F/S machine designs allow the capability to incorporate the addition of pre-molded, pre-sterilized components (inserts) into the basic con-tainer. These inserts, including items such as rubber and silicone stoppers, and tip-and-cap dropper units for eye

CONTINUED Streamlined Blow/Fill/Seal Insertion Technology Increases Flexibility and Safety in Aseptic Packaging of Pharmaceutical Liquids

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drop containers (used to deliver a calibrated drop), are attached to the container after the blowing and filling process, prior to final sealing step. The application of inserts has allowed B/F/S technology to advance and expand into product markets which were previously unavailable, such as intravenous drug administration, solution irrigation and ophthalmic dropper units.

With ophthalmics, the B/F/S insert process enables increased efficiency and sterility control in the pro-cessing of expensive drug formations for treatment of glaucoma and other eye diseases. Other types of sterile inserts can be incorporated into the basic B/F/S-produced container as well, such as top geo-metrics for both bottles and ampoules that can include a multi-entry rubber stopper or a controlled diameter injection-molded insert, useful where multiple admin-istration of a drug is required. The stopper would typically be an FDA-approved, rubber or silicone insert that would be placed inside the bottle or parenteral. Then, at the point of delivery the nurse would stick a needle through the stopper and extract the fluid, or if it is a vascular flush, the nurse would insert it into the patient’s IV set.

Aseptic B/F/S-produced small-volume parenterals (SVP), such as those used for local anesthetics, vitamins, vaccines and other standard injectable products, can be manufac-tured with a twist-off-opening feature. They can also be combined with a controlled-diameter form in the top to accommodate needle-less spikes. Luer locks or luer-slip fits can also be provided for making leak-free connections. For 2 to 5 mL small- volume parenterals, syringes can be con-nected directly to the ampoules without a needle, creating an inherently safer packaging solution.

B/F/S-produced, one piece, plungerless sterile syringes (designed for pre-filling) for use in flushing hospital equip-ment such as catheters, are available for replacing tradi-tional two-piece plunger-type syringes. The B/F/S syringe provides an offset chamber for trapping air, and preventing it from being dispensed during drug delivery.

Advanced B/F/S insertion processes can also incorporate tamper-evident features for multi-dose container closures, offering added security.

Advanced Insertion Isolation Technology The latest generation of Blow/Fill/Seal machines use a modular design, integrating duo Class 100-environment manu-


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facturing processes, and utilizing servo-drive controls with system-integrated PLCs (programmable logic controllers). These B/F/S systems address process monitoring, stream-lined maintenance and consolidated machine components for optimum performance.

They feature advanced insertion technology, incorporat-ing the use of a Class 100 environment isolation chamber located outside of the B/F/S unit, but integrated with the B/F/S machine. This process allows the operator to pres-ent a pre-sterilized (typically with a gamma or an e-beam process) component (stopper or dropper insert) through a secure sterile pass-through into a Class 100 environment for insertion within the B/F/S filling shroud.

Sterile inserts are loaded into the isolator through a dou-ble-locking, sterile rapid transfer port. The inserts are in-dexed into a special track mechanism which transfers them from the isolator into the nozzle shroud of the B/F/S. The filling of the container and the placement of the insert into the container both take place in sequential operations within the nozzle shroud. Each component is inserted into a mold-ed container before the final top closure is formed. The container-insert combination package is then sealed, having given the B/F/S product the intended drug delivery features. The entire operation takes place under Class 100 controlled

environment conditions with no human intervention, provid-ing a high level of sterility assurance for the final product.

Key factors of this isolation technology include minimiz-ing particles generated through moving components, and controlling the air pressure cascade from the isolator to the nozzle shroud, providing enhanced sterility assurance and thereby achieving regulatory compliance. All of the me-chanical features required to get the inserts from the isola-tor into the B/F/S container are enclosed within a Class 100 environment. A servo-controlled fill and insertion system eliminates the need for hydraulics above the mold. Ser-vo-drives deliver the inserts, so belt and chain mechanisms, which typically require lubrication and can generate non-vi-able particles, are eliminated. High-speed PLCs provide integrated control architecture for the entire B/F/S ma-chine. All modular functionality, such as with the insertion isolator, the insert-delivery track system and the B/F/S filling processes are totally integrated for speed and optimum performance. The PLCs receive continuous communication from the B/F/S-isolator system, continually monitoring the differential air pressure in the B/F/S and isolation systems, as well as ensuring that particle counts are under control.

Conventional liquid aseptic manufacturing, with parenterals


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for example, requires filling and sealing to be carried out in a Class 100 environment and necessitates considerable validation efforts. Both the B/F/S machine and the inser-tion isolator do not need to be housed in a Class 100 area because their activities are protected within the machines themselves. This protection considerably reduces the scope of validation requirements.

Sterility and particulate matter are two of the most critical re-quirements for aseptically-produced products, and advanced B/F/S and insertion isolation technology offer distinct advan-tages over earlier systems. This includes maintaining precise control over differential air pressure between the isolator, the insert transport and the B/F/S nozzle shroud. Both the isolator and the B/F/S system are equipped with HEPA air showers to assure a Class 100 environment under dynamic conditions in the isolator, tunnel and nozzle shroud area.

It has been well documented that in the B/F/S process, non-viable particles primarily originate from the electrical-ly heated cut-off knife contacting the molten parison, and that better control of non-viable particulates will provide enhanced sterility assurance for the Blow/Fill/Seal process. The more advanced B/F/S systems use additional technolo-gy in response to FDA concern over particulate contamina-tion during B/F/S fabrication.

Ultrasonic KleenKut® technology can be used to cut the molten parison at ambient temperature, drastically reduc-ing non-viable smoke particles that are generated by tradi-tional hot knife cutting. The process reduces particulates in the cutting area by 99 percent. Non-viable particles 0.3µm to 10µm in size are significantly reduced in quantity com-pared with the volume of particles produced during the use of hot-knife cut-off mechanisms.

Expanding Use of Blow/Fill/Seal Insertion Technology Advanced aseptic B/F/S containers and ampoules can de-liver precise dosing in disposable formats. The incorpora-tion of a sterile tip-and-cap, a rubber stopper or a multi-en-try insert into the B/F/S package offers added flexibility in container design and drug delivery methods, as well as enhanced sterility safety. These benefits are continuing to push the acceptance and use of advanced aseptic B/F/S technology, particularly into injectable product areas and biologics – where proteins and other complex solutions have brought B/F/S technology to the forefront. The B/F/S process offers outstanding versatility for multiple container designs. A unique design feature of the ASEP-TECH® B/F/S systems, for example, permits the insertion process to be suspended without requiring significant equipment


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changeover. This feature allows the production of standard containers without inserts to be produced on the same ma-chine with a simple recipe change.

As the use of advanced aseptic Blow/Fill/Seal processes broaden, insertion technology will become more important as drug producers continue to seek new delivery methods for breakthrough drugs.

About the Author: Andrew W. Goll is Technical Sales Manager for Weiler Engi-neering, Inc., responsible for technical support for the com-pany’s customers worldwide. He has over 18 years of expe-rience in the Blow/Fill/Seal community including research and development, design engineering, and contract and generic manufacturing plant operations. He is a member of the Parenteral Drug Association (PDA) and International Society for Pharmaceutical Engineering (ISPE). Goll holds a Bachelor of Science degree in business administration and a Master of Business Administration degree.

About Weiler Engineering:Weiler Engineering is a worldwide provider of aseptic Blow/Fill/Seal custom packaging machinery for pharmaceutical and healthcare applications. Based in Elgin, Illinois, and founded in 1959, Weiler’s proprietary Blow/Fill/Seal system

is the culmination of 40 years of innovation in machine design and sterile process development, producing a highly advanced aseptic liquid packaging system. Its ASEP-TECH® Blow/Fill/Seal technology integrates blow molding, sterile filling and hermetic sealing in one continuous opera-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 and end-user requirements. These application challenges are met through the offering of several machine models de-signed to manufacture containers ranging in size from 0.1 mL to 1,000 mL at production rates of up to 15,000 units per hour, depending on container configuration.

To reach Weiler Engineering, please contact Chuck Reed, Director, Sales & Marketing; 1395 Gateway Drive, Elgin, Illinois 60124; Phone 847-697-4900; email [email protected]; www.weilerengineering.com


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blow/fill/seal - healthcare packaging that parenterals, injectables, ophthalmic solutions, and...

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