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.
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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).
