Industry Looks to New Blow-Fill-Seal Uses
The versatile technology delivers a variety of low-cost, aseptic containers.
B. Braun makes and fills Ecoflac plus bottles with IV solutions using rommelag Model 364 rotary blow-fill-seal units.
Requirements for convenient treatment options for inhalation therapy, demand for unit-dose packaging for home use, and device system innovation are among the trends promising continued growth for blow-fill-seal (BFS) technology.
Markets have employed BFS for lightweight, easily handled, multiple-dose bottles used in vaccines and IV therapy. BFS vials and ampoules deliver precise dosing in disposable formats for respiratory and ophthalmic treatments used in home and hospital settings.
“Given the predominate focus on reducing healthcare costs, companies are demanding cost-effective packaging and sterile systems that will stay sterile until the point of use,” says Rick Schindewolf, vice president, business development for BFS, Catalent Pharma Solutions (formerly Cardinal Health Pharmaceutical Technologies and Services; Woodstock, IL).
“We see continuing strong presence in respiratory products where generics are driving volume, and from next-generation inhalation products in the pipeline. As mainstay drugs in ophthalmics lose patent protection, generic companies can enter the category without the large investment required for conventional filling equipment,” Schindewolf adds.
BFS is a process in which bottles and vials are typically aseptically molded, filled, and sealed in one step on a single machine. Latest-generation machines from leaders such as rommelag USA (Evergreen, CO) and Weiler Engineering (Elgin, IL) use modular design, integrate manufacturing processes, and feature electrical servo drive controls.
BFS equipment manufacturers and contract packagers have continued to explore new applications.
“Respiratory and ophthalmics are by far the leaders in BFS, but a lot of work is being done in vaccine research. Although glass vials predominate domestically, BFS vaccine packaging is used more widely overseas because it is a very cost-effective, very safe aseptic process,” says Chuck Reed, sales manager for the Americas, Weiler Engineering (Elgin, IL).
“We are seeing much more interest in the injectables product area and in biologics. With the China market opening up, we have seen an increase in nutraceutical-type applications in oral and injectable formats,” Reed adds.
Reed notes that BFS is well suited for delivery system innovations, where the drug might be packaged in a BFS-molded cartridge for insertion into a delivery device. “BFS lends itself to producing a closed aseptic container that can be opened under sterile conditions either in the hospital environment or by the individual,” he says.
Sterile BFS unit-dose packaging is driven by the trend toward home healthcare and the advantages inherent in the single-dose disposable format.
“The standard BFS container for vaccines has been multiple-dose for injection. But there is a move to unit-dose where you have more control over the product, and it is easier to transport, compared with glass containers that are susceptible to breakage,” says Tim Kram, general manager, rommelag USA.
One of a new generation of all-electric machines, rommelagï¿½s bottlepack Model 324 supports easy access with structural tubing and plexiglass walls replacing stainless steel housing.
Kram notes that BFS containers that are destroyed when the caps are broken or twisted address counterfeiting concerns. “FDA likes containers that can’t be reused. BFS precludes people from doing cheap knock-offs because containers can be made in unique shapes, and the technology requires a significant capital investment,” he says.
Increases in asthma and chronic obstructive pulmonary disease (COPD) with the aging population are BFS packaging drivers. Most BFS inhalation drugs are delivered in unit-dose vials for use with nebulizers. Drug nebulization has provided convenience for frail or disabled patients that have difficulty manipulating metered-dose and drug-powder inhalers. A unit-dose vial is poured into a cavity of water in the nebulizer where the drug is converted into a cool liquid mist that is inhaled through a mouth piece or face mask.
Dey L.P. (Napa, CA) announced FDA approval of a new drug application for the Perforomist Inhalation Solution, the only FDA-approved nebulized form of formoterol fumarate for treating COPD. The bronchodilator has been offered in blister-packed dry-powder form used in the Foradil Aerolizer marketed by Novartis. (Generics giant Mylan Laboratories is acquiring Dey from Merck KGaA [Darmstadt, Germany] in a deal expected to close later this year.)
The product is a 2-ml fill in a 2-ml PE vial with a twist-off cap, overwrapped in a foil pouch, says a Dey spokesperson, adding: “Dey has the option of making Perforomist on several different models of BFS rommelag machines.”
In ophthalmics, BFS has proved to be an ideal process for creating packages with highly controlled geometry. Sterilely inserted custom tips support a controlled drop size for tight dosage requirements. Leading eye-care firms such as Allergan and Alcon have in-house capacity for producing BFS unit doses, as well as multiple-dose dropper bottle formats that typically employ conventional bottle and cap packaging, says Schindewolf.
“Currently, there is only one prescription ophthalmic drug packaged in a multidose BFS container,” Schindewolf says.
The unit-dose format avoids the need for preservative systems that can cause eye irritation and reduces the potential for solution contamination.
Adds Gary Casey, CEO, Vital Pharma (Riviera Beach, FL): “Multiple-dose packaging is susceptible to contamination while in use by the patient. We see a strong opportunity for BFS unit-dose formats going forward.”
Unicep (Sandpoint, ID) uses a modified BFS process to provide nonsterile packaging for products such as oral healthcare OTCs and in vitro diagnostics. The company’s MicroDose with a tapered dispensing tip and the TwistTip vial both support unit-dosing convenience.
“Packaging helps sell product, and specialty packaging helps sell product better. Customers are demanding unit dose because people feel is it is more convenient and safer,” says John Snedden, CEO.
“The diagnostic testing market is huge and growing because people want instant results when they are tested at the pharmacy or doctor’s office. These diluents do not need to be sterile, but they have to be packaged with an extremely high level of purity,” Snedden adds.
Product stability in sterile BFS is typically addressed by nitrogen gas blanketing after filling and with barrier pouching. New drug formations including biologics have spurred investigation of alternative materials to the standard LDPE, HDPE, and polypropylene.
Schindewolf heads up an innovation group at Catalent that is exploring new BFS applications and materials. “We are trying to expand the platform for BFS beyond the traditional respiratory and ophthalmic categories, with several new products slated for launch in the next year,” he says.
Cobridge Solution’s EZ Amp, manufactured by Catalent, replaces an earlier version of a bottle with a lure top for saline solution used in catheter flushing. An improved luer-lock top is used in a bottle redesigned to a 10-cm3 size and reshaped to improve collapsibility, says Schindewolf.
Catalent has also had success packaging a biologic drug in a BFS container, says Schindewolf.
“We expect to see opportunities open up in biologics with Washington legislation creating an approval pathway for generic versions of biologics,” says Vital Pharma’s Casey. A Senate committee has endorsed a bill that would expose brand-name biologics on the market for 12 years to generic competition.
“New resins are constantly under development. Product compatibility with the inner surfaces is driving the use of different materials. Some bio-based drugs have adsorption issues with LDPE,” says Kram.
“We have a base knowledge of various mono resins. Then we will work with the resin manufacturers to develop material options. We are testing different new materials as the inside-container layer to achieve compatibility with one drug.”
rommelag features coextrusion technology that has recently been adopted for packaging a sensitive product. The bottlepack Co-Extrusion unit handles up to a seven-layer parison in which the barrier material is sandwiched between layers of PE and PP. Kram says that several machines have been sold for oxygen and carbon dioxide–sensitive injectable drugs that had been packaged with a BFS mono layer and overwrap. The coextruded 20-ml vial employs an inner EVOH layer with LDPE. “EVOH works in preventing oxygen ingress. If you have a small fill, you can’t afford to lose water vapor that will lead to a PH change. COC may be employed for moisture barrier,” he says.
BFS vendors have studied PET (polyethylene terephthalate) for its barrier and high-clarity advantages, but the material remains problematic for products requiring terminal sterilization that melts the material.
“We are stability-testing a monolayer PET with some customers for aseptic filling of sterile products. To my knowledge, no one has put a product out in it yet,” Kram says.
Adds Reed: “Although PET can be blow-molded and has very good barrier, it tends to fracture when you are trying to open the container. It works well in blow-molded bottles where a secondary cap is applied. People are looking at the vacuum deposition of metalized coatings on the BFS package. But this will require a lot of development work before it is commercially available.”
The Asep-Tech Model 628 from Weiler Engineering features a servo-controlled fill system eliminating hydraulics above the mold.
FDA and international regulations have prompted attention on quality management and equipment improvements. FDA issued requirements on aseptic processing in 2004, and ISO standard 13485 provides guidance on BFS processes. “FDA’s guidance and European Medicines Agency regulations have pushed us to improve the science of BFS,” says Reed.
For example, Weiler has introduced its patented KleenKut technology that responds to FDA concern over particulate contamination during BFS fabrication. Ultrasonic technology is used to cut the molten parison at ambient temperature, drastically reducing smoke particles that are generated by hot-knife cutting. “KleenKut is application-specific for packaging made of polyethylene. We reduce the particulates in the cutting area by 99%,” says Reed.
Casey notes that many Vital Pharma customers are requesting ISO 13485 certification. “An FDA audit might be adequate in the United States, but customers doing business overseas are looking for a globally accepted standard. We are ISO 13485: 2003 certified. It challenges you to dig down into your SOPs and validation processes, and puts you in a far better position for an FDA audit,” says Casey.
New-generation model lines from rommelag and Weiler address process monitoring, facilitate maintenance, and consolidate machine componentry.
With the Asep-Tech Model 628, Weiler integrates innovations added over the years to its Model 624. The 628 features a two-piece stepped base for easier maintenance. The servo-controlled fill system eliminates hydraulics above the mold. “The Model 628 has been designed to accept all the 624 tooling. So contract packagers that might be making five or six different products can keep their existing molds, fill systems, and parison heads,” says Reed.
rommelag bottlepack Models 324, 362, and 364 are electric servo-driven units. Structural tubing and Plexiglas walls replace a stainless-steel housing in units with walk-up access to componentry. The models were “built in a computer” for efficient component integration, says Kram.
For high-speed, large-volume parenteral production, B. Braun uses the bottlepack 364 at its Melsungen, Germany, IV packaging plant. The 364 stages bottle fabrication, filling, and sealing as four molds move on a rotating platform. Geared for larger bottles of 50 ml to 1000 ml, the rotary unit increases production speeds significantly, producing 2400 to 10,000 bottles per hour, says Kram.
rommelag’s bottlepack 4010M operates on a vertical plain. As many as 15 molds rotate vertically in a continuous chain. The mold is rotated into the fill area where the parison is being extruded. As one mold forms a container, the next mold comes in with the head mold to form and close off the head of its predecessor and form the next container, in a process in which the parison-cutting step is eliminated. Nitrogen replaces air for ballooning the parison in the mold in an enclosure that prevents air ingress. The process limits nitrogen consumption compared with nitrogen flushing and ensures that the containers contain only nitrogen, says Kram.
Unicep targets lower-volume applications of up to 15 million units per year, for which it can quickly and economically produce custom molds when required. “It’s difficult for someone running 500,000 of 1 million units at a time to find capacity with a large contract BFS packager. The unit cost can be done very efficiently with multiple-cavity molds, but it comes at a very high cost of capital,” says Snedden.
“We develop a single-cavity mold at 5% to 10% of the cost of a high-speed mold and have it ready from concept to production order in 90 days, providing a lower unit cost on smaller-volume orders. Our customers are not paying for the cost of a sterile process,” Snedden adds.
Unicep has developed a vial and applicator system with built-in brush or swab tip for topical treatment of wounds and cuts or for cosmetic uses. The solution will go on line shortly on machines designed and built in house.