a report by

Ch a r l e s H R e e d

Sales Manager, Weiler Engineering, Inc.

Blow-fill-seal technology, originally developed inEurope in the 1930s and introduced in the US in the1960s, has emerged as a preferred method for asepticpackaging of pharmaceutical and healthcare productsdue to unrivalled flexibility in container design,overall product quality, product output and lowoperational costs. The Weiler design incorporates themulti-step process of blow moulding, aseptic fillingand hermetic sealing of liquid products in onesequential operation on a compact, automatedmachine frame with fill volumes ranging from 0.1millilitre (ml) to 1,000ml.

A variety of polymers may be used in the process, lowand high-density polyethylene and polypropylenebeing the most popular. The innate ability to formthe container/closure during the actual asepticpackaging process allows for custom design of thecontainer to meet the specific needs of theapplication. This flexibility not only improvescontainer ease of use, but provides a means ofinterfacing with many of today’s emerging drugdelivery technologies, most notably in the field ofrespiratory therapy.

Recent advancements in machine design allow forinsertion of pre-moulded, pre-sterilised componentsto be moulded into the container creating additionaldesign options to create multi-use and injectableproduct containers. Furthermore, the blow-fill-sealprocess flow is normally impacted by only two rawmaterials, product and polymer, that are eachprocessed inline, thereby making the processamenable to large uninterrupted batch sizes, some inexcess of 500,000 units, and fill durations of up to120 hours. The net effect is routinely an increase inproduction efficiency and a subsequent decrease inoperational costs for the user.

Blow-fill-seal systems represent a niche marketwithin the larger form-fill-seal marketplace forpharmaceutical packaging equipment. The blow-fill-seal process is a robust, advanced aseptic processingtechnology, recognised by worldwide regulatoryauthorities for its inherent operational advantagesover conventional aseptic production. Blow-fill-sealsystems offer a unique combination of flexibility in

packaging design, low operating cost and a highdegree of sterility assurance. The machines require aminimum number of operating personnel and have arelatively small space requirement.

B l ow - F i l l - S e a l P r o c e s s

C o n t a i n e r M o u l d i n g

Thermoplastic is continuously extruded in a tubularshape (see Figure 3a). When the tube reaches thecorrect length, the mould closes and the parison iscut (see Figure 3b). The bottom of the parison ispinched closed and the top is held in place with a setof holding jaws. The mould is then transferred to aposition under the filling station.

C o n t a i n e r F i l l i n g

The nozzle assembly lowers into the parison until thenozzles form a seal with the neck of the mould (seeFigure 3c). Container formation is completed byapplying a vacuum on the mould-side of the containerand blowing sterile filtered air into the interior of thecontainer. The patented electronic fill system deliversa precise dosage of product into the container. Thenozzles then retract into their original position.

C o n t a i n e r S e a l i n g

Following completion of the filling process, the topof the container remains semi-molten. Separate sealmoulds close to form the top and hermetically sealthe container (see Figure 3d). The moulds open andthe container is then conveyed out of the machine.

P r o c e s s P e r f o rman c e

Increasing regulatory scrutiny in the area of productquality, most notably product sterility assurance, haschallenged the pharmaceutical and healthcareindustries to consider alternatives to traditionalmethods of aseptic packaging. Blow-fill-seal has beenrecognised by the US Pharmacopeia (USP XXIV) andthe Parenteral Drug Association (PDA) (TechnicalReport 26) as an ‘Advanced Aseptic Process’, whichmay be defined as a technology that can dramatically

Recent Techn ica l Advancements in B low-Fi l l - Sea l Techno logy

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reduce the potential of contamination from humanpresence during aseptic processing operations due toits design and functionality.

The process reduces the amount of the amount ofproduct-contacting components, there is limitedoperator intervention and the critical fill-zone isphysically isolated under a continuous flow of filteredair. Since blow-fill-seal is a completely automatedtechnology that allows for remote operation it is anideal system for examining the relationship betweenthe level of airborne micro-organisms in the

environment and the product contamination rate. Aseries of published studies have been conducted toinvestigate and quantify this relationship andpotentially provide a means for predicting sterilityassurance levels.1–3

This experimental work was performed byproducing controlled challenges of micro-organismsdispersed in air at concentrations extending over a1,000-fold range in a containment room housing ablow-fill-seal machine producing containers filledwith a medium that supports the growth of thechallenge organisms. Results of the studiesdemonstrated a direct relationship between thefraction of product contaminated and the level ofairborne micro-organisms. The linearity of the curveprovided a reasonable basis for extrapolation. Theresulting predictions imply that a sterility assurancelevel similar to that targeted for terminally sterilisedproduct is achievable with a properly controlledblow-fill-seal process. These challenge studies alsoprovide a means to rationalise machine design andconditions of operation.

Ad v a n c e d T e c h n o l o g y

Good science drives good engineering and there isno room in today’s regulatory environment for the“we have always done it that way” approach to thetechnology. The corporate focus of WeilerEngineering, Inc. is to provide the most advancedaseptic-liquid-processing technology availablethrough the application of customised ASEP-TECH® blow-fill-seal machinery and integratedservices. Weiler Engineering is committed to theadvancement of blow-fill-seal technology and hasestablished a development partnership with theworld leader in blow-fill-seal contract packaging(Cardinal Health Manufacturing Services (CHMS-ALP)) and a top-ranked research firm (AirDispersions, Ltd (ADL)).

This partnership approach has enabled WeilerEngineering to take advantage of a state-of-the-artmicrobial challenge facility (MCF), designed andbuilt at CHMS-ALP to allow detailed scientificassessment of the blow-fill-seal process. The MCF isfully self-contained and includes a machinecontainment room with a closed-loop heating,ventilation and air conditioning system, a chlorine-dioxide decontamination system and a dedicatedmicrobiology laboratory. Advanced controlled

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1 C S Sinclair and A Tallentire, “Predictive Sterility Assurance for Aseptic Processing”, Sterilization of Medical Products,(R F Morrissey, ed.), VI, 1993, Polyscience Publications, Montreal, pp. 97–114.

2 C S Sinclair and A Tallentire, “Performance of Blow-Fill-Seal Equipment under Controlled Airborne MicrobialChallenges”, J. Paren. Sci. Technol., 49 (6) 1995, pp. 294–299.

3 A Bradley, S P Probert, C S Sinclair, and A Tallentire, “Airborne Microbial Challenges of Blow/Fill/Seal Equipment”,J. Paren. Sci. Technol., 45 (4) 1991, pp. 187–192.

Figure 1: Blow-Fill-Seal Containers

Figure 2: Blow-Fill-Seal Machine

Recent Techn ica l Advancements in B low-Fi l l - Sea l Techno logy

airborne microbial challenge studies are conductedunder the research guidance of ADL with staff fromCHMS-ALP and Weiler.1–3

The main characteristic of the blow-fill-seal process,key to its widespread acceptance, is the isolation ofthe critical filling zone within the machine. Sterile airmanagement within this critical zone is typicallyverified through environmental monitoring for thepresence of non-viable particulates. Control of non-viable particle generation within the manufacturingarea has been investigated and detailed in severalresearch papers dating back to the early 1990s.

It has been well documented that non-viableparticles primarily originate from the electricallyheated cut-off knife contacting the molten parison.3

It has been predicated and generally accepted thatbetter control of non-viable particulates will provideenhanced sterility assurance for the blow-fill-sealprocess. Various improvements in machine designhave resulted over the years related to theseenvironmental concerns. Past attempts to managenon-viable particulate generation were targeted tothe removal of particles after they were produced.Included in these improvements was thedevelopment of parison shrouding (pioneered byWeiler Engineering). Parison shrouding typicallyemploys a controlled air environment blower systemwith differential pressure controls in conjunctionwith containment ductwork in the parison cut-offarea to siphon away smoke created by the hot knife.

K l e e nKu t™

The evolution of the technology has now reached anew level with Weiler’s introduction of the patentedKleenKut™ parison cut-off mechanism, which isdesigned to prevent the generation of particulates atthe source. The KleenKut is a cold-knife inventionthat accomplishes the cutting of the parison without

the use of a heated high-resistance wire. A heatedwire cut-off typically produces visible smoke, whichmust then be removed with a shroud/blower system.The KleenKut eliminates smoke generation throughthe patented application of ultrasonics, effectivelyreducing particulate generation at the source bymore than 99%.4

The KleenKut device has now been in place onmultiple high-volume production blow-fill-sealmachines for more than 18 months operating in fullyvalidated processes. Regulatory authorities todayrequire sound scientific data to back up processimprovement claims and additional follow-on studieshave been conducted that provide supporting datafor this new technology. The data shows that directcontact between the KleenKut mechanism and theextruded parison does not cause microbialcontamination of vials and confirms that non-viableparticles 0.3µm to 10µm in size are significantlyreduced in quantity compared with the volume ofparticles produced during the use of a hot-knife cut-off mechanism.5 Currently, KleenKut technology isavailable for both-low density and high-densitypolyethylene resin applications.

P r o du c t A pp l i c a t i o n s

Blow-fill-seal technology has gained much marketfocus in recent years due to the increased focus onbiologics, proteins and other complex solutions.These important products often cannot withstandexposure to high temperatures for extended periodsof time without degradation of their activecomponents. Conventional terminal sterilisation,therefore, is not an acceptable method to produce a‘sterile’ product. Bulk sterilisation, sterilisation bygamma irradiation or filter sterilisation followed bydirect packaging utilising the blow-fill-seal processare often used successfully for these types ofproducts. ASEP-TECH blow-fill-seal machines

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Figure 3: Container Moulding, Filling and Sealing

4 P Poisson, “Non-Viable Particle Management During B/F/S Manufacturing Operations”, BFS News, Autumn Edition,1999, pp. 12–16.

5 P Poisson, C Reed and C Sinclair, “Challenge Testing of the KleenKut Parison Cutoff Mechanism”, Joint Presentation,BFS User’s Group Annual General Meeting, Switzerland, 14 June 2001.

from Weiler Engineering are operating in fullyvalidated production applications demonstrating lessthan a 1ºC temperature rise in a liquid pharma-ceutical active packaged in a 5ml low-densitypolyethylene vial.

Viscous products, with apparent viscosities of lessthan 15,000 centipoise, and suspension products canbe handled by blow-fill-seal machines with speciallydesigned product fill systems. Weiler Engineering haspioneered the packaging of these types of productswith the use of innovative liquid-handling systems tomaintain multiple-component products in ahomogeneous solution during the filling process.Basically, if the solution will flow and if it cantolerate a minimum residence time, it can bepackaged in an ASEP-TECH blow-fill-seal machine.

The product fill systems of the Weiler machines arealso designed to minimise product hold-up volume.Combined with the precision fill accuracy achieved byWeiler’s patented electronically controlled time-pressure fill system, significant savings can be realisedfor processing expensive complex solutions. Fillaccuracies of better than ±5% have been demonstratedfor container volumes as small as 0.5ml.

An c i l l a r y E q u i pmen t

Advancement of blow-fill-seal technology includesthe incorporation of the latest in industry trends.Weiler designs and builds highly integrated finishing

lines to complement the ASEP-TECH machines.Sophisticated materials-handling systems can becoupled with leak detection, vision systems,overwrapping and labeling equipment to providefully functional, integrated production linesrequiring a minimum of operator intervention.Incorporation of 21CFR Part 11 compliant controlsystems is part of the evolution of the DataAcquisition packages now available on ASEP-TECH blow-fill-seal machines.

F u t u r e E f f o r t s

Weiler Engineering, Inc. has held a leadershipposition for more than 30 years, serving themarketplace with the latest in advanced, sterile,aseptic liquid-packaging technology. Several keydesign/development initiatives are currently underway at Weiler, including a continuation of the jointstudies in the MCF facility at CHMS-ALP.

Approximately 100 people are involved in the designand construction of the machines, providing 21stCentury Solutions™ for parenterals, ophthalmics,respiratory drugs, biologicals, nutraceuticals andother complex solutions. Weiler’s manufacturingfacilities and corporate offices in Elgin, Illinois areconveniently located near Chicago’s O’HareInternational Airport. ASEP-TECH blow-fill-sealmachines are designed and built in a new 120,000square foot, state-of-art manufacturing plant. Allequipment is manufactured in the US. ■

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