New technology

The latest BFS technology focuses on controls, container geometry, minimizing particulate generation, and improving the zones of protection around container formation, filling, and sealing. Thus, many machine designs feature dark and white sides. Positioning the extruder, electrical cabinet, and mechanical systems on the dark side in an unclassified area provides easy access for operators without disturbing the white side, which is housed in an ISO 8 (Class 100,000) cleanroom.

In the fill area of the machine, laminar air flow helps maintain ISO 5 (Class 100) conditions. In addition, some machines reduce particulate generation by replacing hot-knife parison cutting with an ultrasonic process. This change reportedly reduces particulate generate nearly 100% (KleenKut parison cutoff technology, Weiler Engineering).

Although most BFS machines are designed to produce monolayer containers, multilayer technology is available to address needs for barrier properties or product–package compatibility issues. Although three to seven layers are feasible, barrier structures typically consist of five layers with a center layer of ethylene vinyl alcohol and can eliminate the need for the foil overwrap normally used as secondary packaging for carbon-dioxide- or oxygen-sensitive products.

Recommendations for newcomers

BFS technology is particularly well-suited for small-volume parenteral ampuls. (IMAGE IS COURTESY OF WEILER ENGINEERING)

To reduce expenses, newcomers to BFS technology sometimes purchase used equipment or request the services of a contract packager, particularly if product volumes are relatively low. Rebuilt and reconditioned machines are updated with advanced controls and meet the latest standards. "Buying rebuilt equipment offers an opportunity to enter the BFS arena at a reduced cost [typically less than $1 million for the machine]," says Bill Grabowski, president and chief executive officer of HealthStar (Braintree, MA), a contract packager of nonsterile BFS products, moldmaker, and rebuilder of Weiler BFS machines. Used machines also may be the answer to tight lead-time requirements because they typically are delivered in six or seven months. In contrast, brand new machines usually are delivered in a year or more.

Hanley advises meeting with vendors for an in-depth introduction to the equipment. He also stresses the importance of studying the entire process when integrating up- and downstream systems, especially if multiple vendors are involved. He recommends that purchasers of BFS technology assess final product configuration, automated inspection, vacuum testing, and overwrap requirements, as well as the possibility of terminal sterilization. In addition, he says, newcomers to BFS need to understand "the amount and degree of process support needed. It's simple to just buy a machine, but very costly and time-intense to put the machine online and meet the [regulatory] requirements for doing so."

Hal Baseman, principal and chief operating officer of ValSource (Downingtown, PA), a firm specializing in validation support, also stresses the need for up-front study to understand the process and the limitations of the line. "You want to be able to eliminate variables or at least control them," he explains, "so it's essential to determine the critical variables in the process and identify what to test." As a result, validation teams should include expertise in risk assessment as well as process development, engineering, and microbiology.

In addition, Baseman says, "regulators expect [validation] study designs with a sound scientific and statistical basis." However, before the validation process begins, it's imperative that the line be running well with a low level of defects. "You can't validate until it's working right," he concludes.

Helpful resources for BFS packaging operations include FDA's November 2008 Draft Guidance for Industry, Process Validation: General Principles and Practices. Although the agency accepts comments on guidance documents at any time, it's in the process of finalizing the draft based on input received as of March 16, 2009.

Process validation, process design, and operation specifically related to BFS systems are the purview of a task force established by the Parenteral Drug Association. The Manufacture of Sterile Pharmaceuticals and Liquid Medical Devices Using Blow–Fill–Seal Technology Task Force is working with the Pharmaceutical BFS International Operators Association and regulators to identify best practices and develop guidance.

Hallie Forcinio is Pharmaceutical Technology's Packaging Forum editor, 4708 Morningside Drive, Cleveland, OH 44109, tel. 216.351.5824, fax 216.351.5684, editorhal@cs.com
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References

1. USP 28 General Chapter <1116>, "Microbiological Evaluation of Clean Rooms and Other Controlled Environments," (US Pharmacopeial Convention, Rockville, MD, 2002), p. 2682.

2. F. Leo et al., J. Pharm. Sci. Technol. 58 (3), 147–158 (2004).

3. Weiler Engineering, "Safeguarding Solutions Through Innovative Packaging" brochure (Weiler, Elgin, IL, 2007).

4. Rommelag, "Bottelpack Packaging System for Liquids" brochure (Rommelag, Buchs, Switzerland, 2006).