Biopharmaceutical Manufacturing Using Blow–Fill–Seal Technology

The authors give special consideration factors affecting blow–fill–seal technology.
Jun 30, 2011

ABSTRACT

For therapeutics administered by certain routes such as pulmonary delivery, plastic ampuls can offer many advantages over glass ampuls, vials, or syringes. Plastic ampuls are manufactured using blow–fill–seal (BFS) technology. The BFS process involves plastic extrusion, molding, aseptic filling, and hermetic sealing in one sequential operation. Unlike small molecules, biological drug products, such as proteins or monoclonal antibodies, are more prone to degradation during processing, which may result in loss of activity or safety concerns. The operating conditions for a BFS process and the nature of plastic ampuls pose many challenges to the stability and integrity of biological drug products. In this article, the authors discuss considerations in the development and manufacturing of biological products using the BFS process, including potential product exposure to elevated temperature, requirements for leak detection, and packaging operations. They also highlight challenges and strategies for BFS process characterization and validation in the context of biopharmaceutical manufacturing.

Biological drug products, such as proteins or monoclonal antibodies, are predominately packaged into vials or prefilled syringes for intravenous or subcutaneous administration. However, some biological drug products must be administered by alternative routes, such as pulmonary delivery in the form of a mist using a nebulizer. In such a case, using plastic ampuls as the primary drug container offers many advantages over vials or syringes. Plastic ampuls are convenient, simple to use, are unbreakable, and child-friendly. One example of biological product supplied in plastic ampuls is Pulmozyme (dornase alfa, Genentech), prescribed for the treatment of cystic fibrosis. Pulmozyme is a sterile, clear, colorless, highly purified solution of recombinant human deoxyribonuclease I (rhDNase), an enzyme which selectively cleaves DNA, and is available as single-use 2.5-mL ampuls. The patient self-administers the drug by simply emptying the entire content of an ampul (one dose) into the nebulizer bowl for delivery. The development of the Pulmozyme formulation and manufacturing process has been previously reported (1).

Plastic ampuls are manufactured using blow–fill–seal (BFS) technology (2). BFS has gained wide acceptance for pharmaceutical solutions (e.g., eye, nose, and ear drops, contact-lens solutions, inhalations, oral, or topical solutions) and household chemicals (e.g., insecticides, detergents, and disinfectants) because it offers many manufacturing advantages, such as high output and reduced human intervention. The use of BFS in biopharmaceutical manufacturing, however, has been scarce. Unlike small molecules, biological drug products are more prone to degradation, which may result in loss of activity. The unique operating conditions and requirements of BFS technology also pose many challenges to the development and manufacturing of biological drug products.

Conventional fill–finish unit operations such as mixing, filtration, and filling, and their potential impact on the product have been previously reviewed (3). This article focuses on specific challenges and considerations associated with the development and manufacturing of plastic ampuls using the BFS process, including elevated temperature, leak detection, packaging, as well as process characterization and validation.

AN INTRODUCTION TO THE BFS PROCESS


Figure 1: Overview of the blow–fill–seal process.
The BFS process involves plastic extrusion, molding, aseptic filling, and hermetic sealing in one sequential operation, as illustrated in Figure 1. The resin material for primary containers is typically received as plastic granules (e.g., low-density polyethylene [LDPE] or polypropylene [PP]). In the extrusion step, plastic granules are fed through an extruder, where they are melted at temperatures above 160 °C. The melted plastic is pressed and extruded through an orifice, resulting in a continuous hollow tube of molten plastic, referred to as a parison (see Figure 1, Step 1). The metal mold then moves to enclose the parison and forms the plastic container of desired shape, aided by either application of vacuum to the mold cavity through small orifices or by blowing sterile air into the container (see Figure 1, Step 2). Subsequently, a parison dye cut will cut the parison at the top, and the mold carrying the unclosed plastic container (at this stage referred to as an ampul) will move to the filling cabinet. In the filling step (see Figure 1, Step 3), the filling needle is inserted into the top opening and solution is discharged into the ampul. The filling needle retracts after the fill completion. The top portion of the mold then comes together to press the plastic and to form hermetically sealed ampuls (see Figure 1, Step 4). The mold then opens and the ampuls are released from the BFS machine and conveyed to the inspection station (see Figure 1, Step 5).