Medical Device Link.

Originally Published PMPN September 2004

Blow-Fill-Seal

Jenevieve Blair Polin

Blow-fill-seal (BFS) describes an aseptic filling process in which hollow containers are blow molded, filled with sterile product, and sealed, all in one continuous machine cycle. The technology is an alternative to conventional aseptic filling and capping operations, often providing cost savings through high output and process efficiency. Equipment and service providers in this industry now stress that their services neither start nor end with BFS.

“What I’d like to focus on is not only what Cardinal Health can offer in blow-fill-seal manufacturing but also what we can offer along the whole spectrum of the product’s lifecycle,” says Rick Schindewolf. Schindewolf is vice president and general manager of Cardinal Health’s BFS contract manufacturing facility (Woodstock, IL). With the acquisition of Magellan Laboratories in 2002, Cardinal Health provides product development services at its locations in Somerset, NJ; Research Triangle Park, NC; and San Diego. Cardinal Health offers its clients services starting with analytical research and formulation development and continuing through commercialization. 

With its acquisition by ProClinical, contract packager Vital Pharma (Riviera Beach, FL) has undergone a similar metamorphosis. “We are now able to offer formulation development, analytical development, and full stability programs. Once a product is launched, we offer complete secondary packaging and distribution. That is a complete vertical integration,” explains William Stringer, Vital Pharma’s president. “For a virtual company, who doesn’t have a laboratory or manufacturing facilities, and even a big pharma company, it’s a real advantage to get all of these services bundled under one roof.” 

Vital Pharma builds its own proprietary BFS machines, the 940 series. The company recently acquired a 55,000-sq-ft office and manufacturing site in West Palm Beach, FL. When fully built out, the site will have close to a half- billion-unit-per-year capacity. The new facility will contain eight cleanrooms, each equipped with a high-capacity 940 blow-fill-seal machine. 

American Plastics Technologies Inc. (APT; Schiller Park, IL) manufactures its own proprietary line of BFS equipment. Rao K. Murukurthy, president of APT, says, “If somebody needs a plan to package something—it can be IV solutions, antibiotics, unit-dose eye drops or ointments—we can set up the whole factory. We have strategic alliances with other suppliers: boiler suppliers, autoclave suppliers, cleanroom component suppliers. We have at our fingertips everything needed for a turnkey operation, and we have technicians ready to go anywhere in the world.”

APT machines are in commercial production at sites around the world, including Mexico, Saudi Arabia, and India. None are yet running product commercially in the United States, but Murukurthy says APT has sold machines to U.S. pharmaceutical customers who are presently in the process of validation. APT’s machines are available in three sizes. Production rates range from 1000 to 5000 bottles per hour. The company keeps three of each size in stock for immediate delivery.

MUSHROOMING DEMAND 

New applications for BFS packaging are born continually. “For all new compounds coming into BFS,” Cardinal Health’s Schindewolf says, “we start by understanding the customer’s requirements for delivery of the particular product. From there, we have to identify a resin that is compatible with both the product and the delivery requirements.”

“Product compatibility with the resin is the biggest limitation of blow-fill-seal,” agrees Anke Henke, general manager of Rommelag USA (Edison, NJ). “But the answer has always been to perform test work. All products are compatible until proven otherwise. Our services include package development, stability studies, validation, and more. Until a product is tested and proved to be incompatible, the product has the potential to be packaged by blow-fill-seal,” Henke asserts. Rommelag (headquartered in Waiblingen, Germany) invented the BFS process. Rommelag and Weiler Engineering Inc. (Elgin, IL) build most of the BFS machinery used worldwide.

New BFS versions of mature products. The biggest U.S. pharmaceutical markets for BFS historically have been ophthalmics and respiratory care products. Rommelag has been building bottelpack machines for blow-fill-seal packaging of ophthalmics for three decades, but those early BFS containers were “typically multidose designs with reclosable caps,” says Henke. A manufacturer of a mature ophthalmic product—for instance, a preserved solution in a multiuse dropper bottle—is not likely to change the product over completely to a new unit-dose BFS format. “A much more popular approach is to launch an additional product offering, such as a nonpreserved version of the solution, in unit-dose BFS containers,” Vital Pharma’s Stringer explains. The unit dose, Rommelag’s Henke adds, “eliminates the need for preservatives in the solution and therefore reduces the risk of possible allergic reactions in patients.”

Sampling. BFS unit-dose vials offer an elegant and cost-effective alternative for sampling. “An ophthalmic is a bit difficult to sample,” Vital Pharma’s Stringer points out, “because you might be giving away a whole prescription in a multidose container and thereby limiting your sales.” Many ophthalmic manufacturers are therefore asking for a unit-dose BFS container, with or without a foil pouch.

Gels, creams, and ointments. BFS packaging is becoming a popular means of packaging unit doses of creams, gels, or ointments. “It’s less expensive, the sterility can be better ensured, and in some cases it might be more functional than the alternatives,” Stringer adds.

Parenterals. Packaging of large-volume parenterals was one of the first uses of Rommelag bottelpack machines. “The packages are environmentally friendly, and disposal or recycling is possible without any pollution risks,” Henke asserts. “Today’s packaging designs allow low wall thickness, ensuring excellent collapsibility and eliminating the need for an air vent,” she adds. Rommelag recently introduced the Type 364 machine developed especially for larger containers. The bottelpack Type 364 is a new high-speed machine with a unique horizontal turntable mold movement that has four rotating molds, thus offering two-and-a-half times the capacity of any other BFS machine for large volumes. The first machines were delivered in 2003 and 2004 for a new large volume parenterals plant. They have been commercially available since 2003.

Most APT machines are used for BFS packaging of intravenous solutions; some are used for ophthalmics. “The growing market we see,” Murukurthy says, “is 100-ml containers for ready-mixed antibiotics for intravenous administration.” Customers moving away from PVC bags, Murukurthy says, may find BFS an attractive alternative. “The materials used for BFS systems are much more user-friendly than the PVC,” he asserts.

Novel drugs and devices. “One of the strengths of BFS in general is its ability to be configured in a wide range of geometries,” says Chuck Reed, sales manager, Americas, for Weiler Engineering. “With the advent of all of the unique materials that are being developed on the protein side and in particular biomedical devices, we’ve been challenged to develop a lot of different container geometries to fit into different devices to be used for different types of delivery. We encourage people to think of the BFS part of the process as the way to containerize the drug for whatever delivery device they might wish to use.”

Rommelag has developed unique BFS designs for a number of novel applications, including containers with long nozzles for connections to catheters or applicators for products administered vaginally or rectally. 

Vital Pharma manufactures BFS containers for reagents that are part of a collection device for a point-of-care diagnostic test kit. Once the sample is collected, the integrated collection device, including the BFS component, is inserted into the diagnostic kit, which provides an immediate test result.

Insertion technology. Weiler and Rommelag machines incorporate insertion technology to expand the capabilities of BFS components. Tips and caps, needles, and rubber stoppers are just some of the components mated to BFS containers. “We can insert various closures into the semimolten top of the BFS vial after it’s been filled and still have a hermetically sealed vial that is filled in a class 100 environment. That gives a lot of flexibility to what you can do with BFS,” explains Cardinal Health’s Schindewolf. 

Cardinal Health has the patented Smart-Amp, a proprietary design for a vascular flush device. The company hopes to license it for packaging of other parenteral drugs, not just saline. “We could actually use that closure and bottle design to package many different parenteral products,” Schindewolf adds.

Respiratory care. “We’ve seen an expansion in the generic respiratory market, which is driving a considerable amount of volume,” Schindewolf says. “The market has expanded as home healthcare has gotten into the mainstream with BFS and unit-dose respiratory vials. Albuterol and ipratroprium are two very frequently prescribed drugs on the Medicare schedules for the treatment of asthma and COPD. Asthma is one of the growing chronic diseases in the United States, as well as COPD.”

FOIL POUCHES 

Sepracor Inc. (Marlborough, MA) launched Xopenex (levalbuterol), a chiral form of albuterol, in 1999 in blow-fill-seal LDPE unit-dose vials contract manufactured by Cardinal Health. The unit doses are packed 12 to a foil pouch. Cardinal Health uses uses nitrogen throughout the processing and pouches the product in a nitrogen blanket. 

In August of this year, Sepracor launched an individually pouched concentrated unit-dose form of Xopenex (1.25 mg concentrate in 0.5 ml solution). Albuterol was originally sold in multidose 20-ml bottles of preserved concentrated solution. From that bottle, the user dispensed 0.5 ml into a nebulizer and added saline to achieve the desired volume. Those multidose bottles have virtually disappeared, but customers still wanted a concentrated formula, explains Walter Piskorski, vice-president, manufacturing operations, Sepracor. “We created this product to go after the multidose market. It gives the users more flexibility as to the volume they want to deliver,” he explains.

Cardinal Health contract packages the 0.5-ml Xopenex concentrate in a petite, teardrop-shaped BFS vial. It is similar to vials that have been used for years for ophthalmic products. A large “X” on the twist-off top distinguishes the vial, as does an extended tab embossed with product identification information. To make the tiny foil pouch required for this product, Cardinal Health invested in new pouching equipment. 

This product is primarily aimed at the hospital market. Singly pouching unit doses, of course, consumes more foil rollstock than does pouching lots. Piskorski estimates that the cost to singly pouch is about 20% greater than the cost to pouch in groups of 10 or 12. “The actual cost of product is not always the determining factor in a hospital’s decision,” he explains. The individually pouched and bar-coded product may cost more but may save the hospital money. It minimizes missed charges to patients and reduces product waste due to expiration of opened multidose packages. 

Foil pouching will always be a desirable enhancement for some BFS products because of FDA’s concerns about the readability of embossed vials. “I think you will see a continuing move toward single pouching for the hospital market,” says Schindewolf. “Single foil pouching can help reduce confusion and help nurses ensure that the correct product is administered to the patient.” 

Foil pouching adds other benefits as well. “If a customer is concerned about stability, we always suggest putting the BFS unit in a pouch,” Vital Pharma’s Stringer points out. The use of a foil pouch might also enhance a BFS container’s tamper resistance and might protect against counterfeiting, he adds. 

THE PROMISE OF PET AND MULTI-LAYER PACKAGING

The resins of choice for BFS are polyethylenes (LDPE or HDPE) and polypropylene. Contract BFS manufacturers are aggressively exploring the possibilities of polyethylene terephthalate (PET) as an alternative resin. With its crystal-clear glasslike appearance and its superior barrier properties as compared with LDPE, PET may be suitable for products that are not compatible with polyethylene. Furthermore, a foil pouch may be unnecessary for enhancing stability if a BFS container can be made of PET.

Cardinal Health, Vital Pharma, Rommelag, and Weiler are all developing PET prototypes. The challenge is the rigidity of the material. “That’s where the design factor comes in: how to develop the mold and the ergonomics of the container to make it squeezable to deliver the material,” Vital Pharma’s Stringer says. “We are developing the in-house knowledge required to use that resin. We are determining how it is extruded, what the mold design needs to be to use that resin, and the other processing parameters that need to be developed.” 

Weiler’s Reed says a further area of concern with PET is, “How do you make the opening feature reasonably clean and convenient? The nature of PET is that it creates a challenge for producing a frangible web in the area of the twist-off or snap-off top.” He sees the greatest promise for PET in device applications, “where the opening feature is not necessarily critical,” he says. 

“We are interested in focusing our BFS development activities on compounds with more-complex processing requirements such as injectables and biologics. Those products are more likely going to require a different look and feel than LDPE,” Cardinal Health’s Schindewolf points out.

Rommelag has developed a coextrusion BFS machine to produce multilayer packages that include a barrier layer to protect oxygen-sensitive products and to minimize vapor evaporation during shelf life. “PET packages are one option, but multilayer packages are better in protecting sensitive products,” Henke says. “Aside from extended stability, we see the possibility that such multilayer packages can replace the present pouching of unit-dose ampules. This could allow manufacturers to get back to conventional labeling of such ampules, thus eliminating the concerns about the readability of embossed vials.”

As the use of BFS continues to expand into new product areas, suppliers will continue to explore new materials, technologies, and designs to meet the growing needs of this packaging segment. 

Copyright ©2004 Pharmaceutical & Medical Packaging News