Blow-Fill-Seal Packaging: A Sterile Environment
The flexibility and sterility of blow-fill-seal packaging makes it suitable for a wide variety of packaging applications.
Kassandra Kania, Managing Editor
As FDA continues to develop more-stringent sterility standards, pharmaceutical manufacturers are being challenged to find the most cost-effective means of packaging their products while at the same time meeting these requirements. This, as well as developments in drug-delivery systems and the increase in unit-dose packaging, has contributed to the growth of blow-fill-seal technology as a method of choice for aseptic liquid filling. "With the innovations in delivery devices, the flexibility of plastic packaging allows you to interface with [those devices] very easily," says Patrick Poisson, senior project manager, Cardinal Health Sterile Technologies, formerly ALP (Woodstock, IL). "Customers are coming to us requesting containers that can link up with different delivery devices."
The blow-fill-seal process not only allows greater freedom in package design, but it also reduces the risk of contamination and provides a more economical alternative to conventional aseptic processing. Chuck Reed, sales manager for Weiler Engineering (Elgin, IL), sums it up this way: "It combines the flexibility of packaging design with low operating cost and an added degree of sterility assurance due to the fact that it's a multistep process done in one machine frame."
Blow-Fill-Seal vs. Conventional Aseptic Processing
Cardinal Health’s blow-fill-seal process automatically inserts sterile injection-molded components for multiple application containers.
In the chapter "Blow/Fill/Seal Aseptic Packaging Technology," from the book Aseptic Pharmaceutical Manufacturing (Interpharm Press, July 1987; out of print), Frank Leo of Cardinal Health Sterile Technologies defines blow-fill-seal as "the technology and related equipment and procedures in which the formation of the container, its filling with liquid pharmaceutical material, and the subsequent formation and application of a seal for the container are achieved aseptically in an uninterrupted sequence of operations without exposure to nonsterile environments between operations."
One obvious advantage of this process over conventional methods is the reduction in the number of parts required to assemble the package. "With blow-fill-seal, you produce a one-piece, aseptically filled container with a built-in safety seal," says Jeff Price, director of engineering and business development for Vital Pharma Inc. (Riviera Beach, FL). "Conventional aseptic filling typically requires at least three components; vial, cap, and safety seal, all of which need to be inventoried and then sterilized prior to filling."
Frank Harmon, vice president and general manager, Cardinal Health Sterile Technologies, agrees that blow-fill-seal offers a cost advantage over conventional aseptic processing. The other primary advantage, he says, is that it is recognized as advanced aseptic technology; therefore, its level of sterility assurance is greater than conventional aseptic filling. With conventional methods, the product, container, and closure are sterilized separately and then brought together, increasing the likelihood of contamination. With blow-fill-seal methods, there is no need to move the containers from one place to another.
Anke Henke, general manager of Rommelag (Edison, NJ), explains that the entire blow-fill-seal process takes place simultaneously in one compact automated machine under almost total exclusion of the human factor: "There are no parts to take off, autoclave, and put back into the machine," she says. "Cleaning and sterilization of all pathways that come in contact with the product is done in place (CIP and SIP). In addition, our machines have automated/operator-free start-up procedures within the classified area. The modular machine designs facilitate easy separation of the machine between the filling process and the technical side, which houses hydraulics, pumps, valves, etc. That in itself reduces particles even further. And, during production, human intervention is not required in the aseptic area because adjustments, should any be necessary, can be handled by the operator via a remote-controlled visualization system from the technical side. Thus, the operator neither needs to gown up nor does he have to enter the cleanroom for such adjustments."
Blow-fill-seal technology is commonly used for ophthalmic and respiratory drugs, and it is also being employed for parenterals and dental and veterinary products.
Rommelag’s Bottlepack machine blowmolds, aseptically fills, and hermetically seals containers in a variety of different shapes and sizes.
According to Harmon, the blow-fill-seal process is suitable for heat-sensitive products: "We are currently manufacturing several biological products that are very heat-sensitive with successful stability profiles and analytical results," he says. During the process, the cooling of the container begins instantaneously as it is formed into its specific shape, he explains. "The product temperature increases slightly during the initial filling process, but it is not enough to become a detriment to the quality of the drug," says Harmon.
Since blow-fill-seal technology is suitable for unit dose, its use is increasing as more and more companies move to single-use packages.
Steve Dilts, director of marketing for Unicep Packaging Inc. (Sandpoint, ID), credits in part the increase in the use of blow-fill-seal technology to increased demand for unit doses. "Some of the growth we're experiencing is coming from companies that have preexisting multidose packaging and now are looking to go to unit-dose packages."
The company offers two types of blow-fill-seal packaging: The MicroDose package and the Twist-Tip vial. These packages are made using a modified blow- fill-seal process. As Dilts explains, "In our process, sealing takes place after the container is formed and filled, using a proprietary system that localizes heat to the tip area." Unicep's process operates at low temperatures and incorporates several fill systems, allowing flexibility in terms of the volatility and viscosity of products that can be packaged. Limiting the heat and dwell exposure minimizes processing impact to the product. Although the process is non-aseptic, the company has a number of customers that will send their products out for secondary sterilization via gamma or E-beam, he says.
"The MicroDose package has a long, tapered dispensing tip for topically applied products," says Dilts. Veterinary Products Laboratories is using the MicroDose packages for Tissumend, an absorbable tissue adhesive for surgical procedures. The prefilled pipettes consist of a small bulb with an extended tip intended for precise application. "We wanted a prefilled pipette that would contain our adhesive without any problems," says Craig Woods, staff veterinarian and director of business development. The pipettes are placed in nitrogen-flooded pouches and then packaged in cartons.
One of the more recent advancements in blow-fill-seal technology, says Cardinal's Harmon, is the ability to insert sterile packaging components into the container to make it a multiuse container. "Eye-dropper tips or any component of that nature can be manufactured off-line and then sterilized," he says. "Then the component can be transferred to the blow-fill-seal production line and assembled aseptically during the process."
Weiler Engineering's Reed advises companies that are considering blow-fill-seal packaging to make sure their product is compatible with the resin material that is used to form the container. "The next step would be to select a typical container as a starting point," he says. "A custom design can be considered for the container, depending on the delivery method. For example, you may need a vial or ampule with a luer fit. If it's going to be for respiratory therapy applications, typically a twist-off tip is needed so the product can be added to a nebulizer."
Experts agree that the flexibility of the blow-fill-seal process as well as the sterility advantages and low cost make it an excellent choice for a wide range of products that require aseptic processing.