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New advanced aseptic manufacturing technologies are available for filling liquid pharmaceuticals, including biologics.
In blow-fill-seal (BFS) technology, which is a form of advanced aseptic manufacturing, the container is formed, filled, and sealed in one continuous, automated system. A primary advantage of this technology is reducing human intervention, which reduces the risk of microbial contamination and foreign particulates. BFS has long been used in liquid pharmaceutical applications, including small containers, such as ophthalmic and respiratory drug ampoules, as well as larger volume containers, such as saline or dextrose solutions. More recently, BFS technology has been expanding into injectables and into biologics, including vaccines and monoclonal antibodies (mAbs).
Replacing glass vials
Catalent, which has used BFS for more than thirty years, recently launched ADVASEPT, a new technology for "glass-free delivery" of injectable drugs, using BFS technology. The aseptically filled polymeric containers reduce or eliminate many of the concerns associated with traditional glass vials, including the potential for glass-particulate contamination and accidental breakage, the company noted in a press release. Because the technology involves a new container closure, the stability of the drug needed to be measured in the polymer container to identify any concerns with permeation or extractables and leachables. Catalent's analytical group developed test methods for determining an extractables and leachables profile, and a two-year stability study comparing plastic and glass containers for biologics is underway, said Bill Hartzel, director of strategic execution, Sterile Technologies, at Catalent, in an interview with Pharmaceutical Technology. After nine months, the data continues to be positive and shows comparability of the mAb in a glass vial to an ADVASEPT vial.
"BFS technology embraces quality-by-design principles," adds Hartzel. "It simplifies the manufacturing process by reducing variables and removing human intervention and is heavily based on automation. We have challenged the system and identified the critical control parameters to provide enhanced sterility assurance. This proprietary filling technology is designed to drastically reduce the level of foreign particulates in the vial compared to traditional glass vial manufacturing."
Blow-fill-seal for biologics
BFS technology is beneficial for biologics, which typically cannot withstand terminal sterilization and must be processed aseptically. Although there have been concerns that the container is at an elevated temperature during the filling process, much development work has been done to control the impact of heat exposure. Tightly controlling the process is crucial in heat-sensitive applications, noted Chuck Reed, director of sales and marketing at BFS-equipment manufacturer Weiler Engineering, in an interview with Pharmaceutical Technology. Weiler's system controls process parameters, such as incoming product temperature and mold temperature, and has been successfully used for heat-sensitive materials for more than 20 years, says Reed.
Catalent has been supplying a commercial biologic using BFS technology for nearly 20 years. "A challenge with large molecule products is the difficulty in extrapolating the data across molecules, and it is important to understand the process to evaluate whether the biologic is suitable in BFS," explains Hartzel. "Through its understanding of the process, Catalent has proven experience with filling commercial biologics using BFS and continues to provide additional testing on mAbs to provide confidence that this technology is suitable for biologics."
Sterilization and cleanroom operation
To enable aseptic processing, BFS equipment is operated within a cleanroom. In addition to product characteristics, container design, and equipment parameters, the production environment in the cleanroom, including controlled room temperature and humidity, is important to consider, notes Josef Trapl, technology manager for the LifeScience segment at engineering and construction firm M+W Group. For producing biologics, both GMP and biosafety requirements must be considered, and an interdisciplinary engineering approach should be used for correct integration of the equipment in the cleanroom and safe operation of the facility, says Trapl.
Inside the cleanroom, the product-contact path of a BFS system is typically sterilized in place using steam. In addition, the fill area of the system is a crucial section for maintaining sterility. The fill area has traditionally been manually sanitized. Weiler, however, recently introduced a patent-pending, automated system using nitrogen dioxide (NO2) sterilization to both sterilize and depyrogenate the fill area, which provides additional assurance of sterility. NO2 sterilization has low residual sterilant and is thus particularly suited to biologics, which can be sensitive to residual sterilant in the fill area, notes Reed. Noxilizer's NO2-based NOX FLEX Rapid Biodecontamination system is now an option on new Weiler ASEP-TECH Blow/Fill/Seal machines. Noxilizer and Weiler presented results of a study using the new system in a poster, "Decontamination and Depyrogenation of an ASEP-TECH Blow/Fill/Seal System," at the 2014 PDA Annual Meeting in San Antonio, Texas, and the July issue of Pharmaceutical Technology will include an interview with the companies.