Blow-Fill-Seal Technology for Unit Dosing
With benefits such as lower costs, increased safety, and a wide range of shapes and closures, BFS packages are replacing conventional glass vials.
Increasing demand for unit dosing, especially for ophthalmic and respiratory therapy products, has led to the growth of blow-fill-seal (BFS) packaging. While BFS is not limited to production of unit-dose packages, it has come into its own for this application. It is a robust process that is inherently aseptic. It is also an economical approach for unit-dose packaging.
Manufacturers of BFS equipment and contract manufacturers offering BFS packaging are expanding the range of products for which this technology is suitable. To do so, they are mastering the use of a wider array of resins and are pioneering techniques to fill even highly viscous products. They are also custom engineering every bottle shape imaginable and creating designs that marry BFS containers with creative closures or metal or rubber components.
Blow-fill-seal technology combines blow molding, sterile filling, and hermetic sealing into a single process to produce a sterile package. Process inventor Rommelag (Edison, NJ; Waiblingen, Germany) and Weiler Engineering Inc. (Elgin, IL) build most of the BFS machinery in the world. Brevetti Angela Srl (Arzignano, Vicenza, Italy) is a relative newcomer, supplying BFS equipment. Vital Pharma Inc. (Riviera Beach, FL) is a BFS contract manufacturer that builds its own proprietary BFS equipment.
Blow-fill-seal offers several advantages over conventional aseptic processing in glass. One is cost. The cost of producing a BFS container is—depending on BFS machinery capacity—dramatically lower than the same size container in glass. Part of the cost savings stems from the use of a single piece of machinery as opposed to individual machines for filling, stoppering, and capping. Automation also eliminates the need for much of the human intervention required in conventional aseptic filling, contributing to a higher sterility assurance level compared with conventional aseptic processing. The weight of a BFS container is much less than glass, generating further cost savings.
Unit-dose packages often do not require the use of preservatives in the solution, thus eliminating the risk of allergic reactions that are caused by these ingredients, which are typically included in other packages.
BFS also provides an extra measure of safety by greatly reducing the possibility of breakage. “Especially in the hospital, for instance, we’ve seen great acceptance of ampules in polypropylene as opposed to glass, which can provide an opportunity for shards to be part of the injected fluid,” observes Chuck Reed, Weiler’s sales manager.
According to Anke Henke, general manager of Rommelag USA, BFS packages are “light in weight, almost unbreakable, and have good collapsing performance,” making them a first-choice product all over the world.
VOLATILITY AND VISCOSITY
Not all products are candidates for BFS packaging. Volatility and viscosity are two limiting factors.
“For our equipment, we do not recommend that anything with an alcohol content higher than 5% be packaged because of the flammability risk,” stresses Weiler’s Reed. (See sidebar, “Defusing a Volatile Situation,” page 38.)
However, according to Henke, “Rommelag has built explosion-proof- design BFS machines since the 1970s, filling solutions with an alcohol content up to 95%. With standard cleanroom ventilation systems it should also be possible to fill pharmaceutical liquids with a high alcoholic content in plastic packages.”
Viscosity can also be an obstacle, which BFS manufacturers are working to overcome. “Our upper limit for viscosity with electronic time pressure fill is about 15,000 centipoise,” Reed estimates, “but that’s apparent viscosity. Some materials are thixotropic, like ketchup; once you get them flowing they move freely.”
Rick Schindewolf is vice president and general manager of the Cardinal Health Biotechnology and Sterile Life Sciences facility in Woodstock, IL. Formerly owned by Gary Weiler of Weiler Engineering, the firm is now the largest BFS aseptic pharmaceutical contract manufacturer in the United States. “We evaluate viscosity on a case-by-case basis,” says Schindewolf. “We’ve done some extremely viscous products with some modifications to fill systems.”
Rommelag has addressed the problem by developing a special high-viscous-product dosing system to fill eye ointments, vaginal creams, and the like at viscosities up to 800,000 cP.
Henke reveals that for some products, slight warming may temporarily reduce viscosity enough to allow filling. Bill Stringer, president of Vital Pharma, suggests caution regarding this approach, however. “The formulator of the product may have used viscosity to stabilize a suspension,” Stringer explains. “If you warm that, and it becomes thinner, all the solids precipitate out of suspension and stability is compromised.” He adds that Vital Pharma also has “proprietary technology that allows us to fill highly viscous creams and ointments.”
ENHANCING PRODUCT STABILITY
|Cardinal Health Biotechnology and Sterile Life Sciences offers an assortment of BFS packages.|
Polyethylene, ranging from low to high densities, and polypropylene are the standard resins used for BFS. The semipermeable nature of these materials has posed some problems in the past. Migration of gases and vapors into and out of the product may cause a pH shift, degradation of product, or contamination of product by leachables and extractables from inks and glues in secondary packaging.
Many manufacturers use a foil laminate pouch as secondary packaging to combat these possibilities. Jeffrey P. Gilbard, MD, founder and CEO of Advanced Vision Research (Woburn, MA), markets TheraTears lubricant eyedrops in four single-use low-density polyethylene BFS containers sealed within a foil laminate pouch. Without the pouch, loss of both water and bicarbonate, in the form of oxygen and carbon dioxide, would compromise the product. Before developing TheraTears, Gilbard found that other eyedrops on the market, which are not pouched in foil, quickly become hypertonic when these essential components were lost. “The whole problem for a dry eye is hypertonicity,” he says, “so when you take an eye that has a problem with hypertonicity and you put a hypertonic drop in it, you’re not really going to help that person.” He therefore felt that the foil laminate pouch was an essential part of his product packaging. “We meticulously copied the electrolyte balance in the tear film, made it therapeutically hypotonic, and then meticulously worked to maintain that balance and tonicity in the solution on the shelf,” Gilbard stresses.
Dey LP (Napa, CA), a leader in the use of BFS products for the respiratory-care industry and first into market for respiratory generic drugs, will soon offer its entire BFS product line in individually pouched packaging. “Providing the highest quality unit-dose products for our customers is a top priority for us at Dey,” comments J. Melville Engle, president and CEO.
For Nephron Pharmaceuticals (Orlando, FL), the main goal driving the choice of a foil pouch was to prevent contamination by migration of volatile impurities from the inks and solvents that are used in printing cartons and inserts. Nephron uses a polyester/foil/sealant layer lamination from Flexicon (Cary, IL) to form individual pouches for unit-dose BFS vials of albuterol and ipratropium, as well as unit-of-use vials of concentrated albuterol. Nephron produces the unit-dose vials in-house on Weiler BFS equipment.
A side benefit of the foil pouches soon became evident to Nephron. “We saw the advantage of the secondary packaging protecting the product, and then we took that one step further and found that by individually pouching those products, we could offer our customers bar coding of the individual product so that it could be recorded bedside when it was administered to the patient,” recalls Steve Simmons, Nephron’s president.
The pouches also help ensure proper product administration. “With a foil pouch for each individual vial, you have complete dosage and administration instructions as well as product identification on the pouch,” Simmons adds. “Many customers are using two, maybe three vials of different drugs, and they may have them lying on their tabletop by their bedside or easy chair, so they need a way to identify exactly what it is they are administering.”
Foil laminate pouches are not the only means of protecting product stability. Weiler offers the option of modified-atmosphere packaging for oxygen-sensitive products, such as vitamins. In this process, the machine supplies a blanket of inert gas (nitrogen) during the product fill. “Then the customer would immediately overwrap the product in a modified-atmosphere pack or a foil package with an oxygen scavenger,” Reed explains.
Rommelag also builds machines that allow the use of nitrogen during the container-forming and -filling processes. “All Rommelag machines allow nitrogen flushing; however, our rotary-type Model 4010M is the ideal machine for this purpose. Due to the special BFS process in this machine, container forming and filling are performed entirely in a nitrogen atmosphere inside the extruded parison, thus the molded package and filled product is never exposed to the ambient air,” Henke says.
Rommelag recently designed a BFS machine that incorporates coextrusion to produce a vial with enhanced barrier properties. A traditional BFS machine has only one extruder. “With this process,” Rommelag’s Henke explains, “you have several extruders on the machine, because you are extruding a plastic parison consisting of various layers, including a barrier layer. Depending on the specific barrier requirements, different barrier materials are used.”
Vital Pharma offers another option with greater barrier properties than the semipermeable standard resins: polyethylene terephthalate (PET). “We’ve experimented enough to where we’ve actually got that working and we’ve got prototypes in PET,” Stringer says. Product stability is what drives this experimentation, Stringer adds. “We have a client right now that has already demonstrated stability in high-density polyethylene and they know that the product is not stable in low-density polyethylene.”
Rommelag performed first tests for PET processing in the 1970s and has intensified the development of PET container forming during the past years. A special test machine is available for PET tests. “We see good potential for multidose drop packages or cosmetic applications because, apart from greater barrier properties, those packages show excellent transparency, contributing to an attractive product presentation,” Henke says.
Innovative engineering to create custom closures and unique containers has further expanded the potential applications of BFS technology. Weiler has patented an insertion technology that allows the marriage of another sterile component—a tip-type cap or even a metal component—with the BFS container. The secondary parts are introduced to the BFS machine by way of an isolator box custom engineered by Weiler. (For more on barrier isolation technology for aseptic processing, see “Isolator Technology for Vial Filling,” PMPN, November 2002, page 36.) After product filling, the additional component drops into place. Then the seal mold closes so that the secondary part becomes an integral element of the BFS unit.
Insertion technology can also be used in Rommelag BFS machines for the addition of rubber stoppers, dropper parts, and nozzle parts. An isolator system for insertion part feeding is combined with the BFS machine. “We also have inserted a needle into a bellows design to be used for vaccines,” Henke explains. In this design, the needle is shrouded within the sealed closure of the BFS container. “The needle stays sterile until the user twists off the top,” she adds.
Rommelag and Weiler offer machines that can put a luer fitting onto a BFS vial, creating an economical alternative to the traditional capped vial or prefilled syringe. Rommelag’s Henke explains one of the many advantages of this approach: “With a traditional glass vial with a rubber stopper, the nurse must attach a needle to a syringe and withdraw the product, then discard the first needle and attach a second needle in order to inject the drug into an IV bag or into a patient. Using the BFS vial with the luer fit, she attaches the syringe to the luer fitting without the needle and withdraws the product. Then she attaches the needle for administration. Therefore this packaging option eliminates one needle.”
Vital Pharma has incorporated its pioneering design in this area into a vascular access flush device called Vasceze. This product attaches to a medical device.
With all this innovation, the demand for BFS is growing. Weiler consolidated its operations two years ago from five separate buildings to one new 120,000-sq-ft facility for the manufacture of Asep-Tech BFS machinery.
Meanwhile, Cardinal Health has added significant capacity. The company purchased a multibuilding campus facility in Puerto Rico, where it offers multiple contract manufacturing delivery technologies. The facility houses four BFS suites, using three Weiler 640 machines and a Weiler 624 machine, “so we’re talking about 260 million units worth of capacity a year,” says Cardinal Health’s Schindewolf. “We’ve committed about three-quarters of that capacity, but we’re also adding capacity here in Woodstock, by upgrading to newer equipment with greater capacity as well as by adding new Weiler machines.”
Vital Pharma has seen its business double over the past few years, and during the past five years, Rommelag has doubled its machine assembly area for BFS manufacturing in the German and Swiss facilities. This enables the company to not only expand production capacity for its bottelpack BFS machines, but also for in-line leak-detection systems and welding machines.