Aseptic fill–finish activities for parenteral drugs include numerous operations, such as final formulation, filtration, product transfer, and dose determination. With the success of single-use systems in biopharmaceutical API manufacturing and the consequent increased confidence in the technology, it is not surprising that pharmaceutical companies have growing interest in extending the benefits of disposable equipment to downstream operations, such as aseptic filling. Advances in pump designs and other technologies have made it possible for equipment manufacturers to respond, and single-use components for mixing, filtration, fluid transfer, dosing, and sampling are now available.
Magnetic, disk, lightning, and levitating impeller mix systems can be used with disposable bioprocess containers, and technology is available for the addition of both powders and liquids in closed or open systems. Single-use filtration systems have been used in aseptic fill–finish operations for many years and are based on well-established technologies. For filling, the choice of pump technology is important. Advances in peristaltic pump designs have made these systems attractive for single-use aseptic dosing as an alternative to reusable positive-displacement pumps or time/pressure filling systems. Newer diaphragm technology is receiving growing interest, however, as a way to reduce particulate formation, according to Justin Hutchinson, associate director, product management for cell culture and bioprocessing at Thermo Fisher Scientific. Some manufacturers offer pre-validated, pre-assembled, and pre-sterilized single-use diaphragm pumps that fit into existing stainless-steel pump housings. For sampling, systems that have been used in biopharmaceutical API manufacturing are suited to aseptic applications.
There are many benefits to adopting single-use technology for fill–finish operations, many of which are similar to those associated with manufacturing operations. “At the top of the list are the reduction in validation requirements and the elimination of clean-in-place/steam-in-place processes,” notes Hutchinson. “Indirect benefits are realized as well, such as a dramatically reduced fill and finish process turnaround times,” he adds. “Overall, compared to permanent setups, single-use aseptic filling systems require much less space and labor to operate, generate less waste, have a shorter turnaround time, require less documentation, and have a reduced risk for cross-contamination. Together, these benefits add up to increased efficiency and productivity, and reduced cost,” notes Brandon Pence, Thermo Fisher Scientific’s director of global marketing for cell culture and bioprocessing.
New pumps and needles
Many of the same challenges that stainless-steel parenteral filling operations face also exist for single-use aseptic filling, namely, particulates and extractables/leachables. Advances in peristaltic pumps in terms of rate of filling have led to their widespread adoption in single-use aseptic-filling systems. These single or multiple head pumps operate by pushing liquid through a flexible tube with a hardened roller. Natural variations (diameter, wall thickness, and flexibility), stretching, compression, fatigue, and wear of the tubing can lead to inaccurate filling and the generation of particulates, however.
“One solution is the use of disposable diaphragm pumps that rely on pressure to move the liquid, thus eliminating the particulates issue while maintaining filling accuracy,” says Hutchinson. For the filling of larger bags or containers, a system based on a gravimetric volumetric fill principle that does not rely on any type of pump or pressurization can be implemented. In this case, the level of the sterile parenteral drug in a reservoir (fed by a sterile holding tank) and in several measuring tubes is carefully controlled using sensors to ensure accurate and reproducible filling volumes.
For all of these filling methods, recent developments in single-use filling needle technology have also led to improvements in speed and accuracy.
The integrator’s role
The components of single-use aseptic fill–finish systems are provided by many different vendors. An integrator such as Thermo Fisher Scientific, which is familiar with the range of components from these numerous suppliers, is situated to assemble customized systems for the final formulator. “Integrators help customers design single-use aseptic-filling systems that meet their needs in terms of volume, filling rate, and level of automation. We then assemble the systems, sterilize them using gamma irradiation, and then package them for use in the customer’s cleanroom,” Hutchinson explains. He also notes that, with a packaged single-use system, a manufacturer can begin aseptic-filling operations in about 8-10 hours, a much shorter time frame than is necessary when using permanent equipment.
Once a customized aseptic-filling system has been assembled, it is the job of the integrator to sterilize the system using validated gamma irradiation processes. For some single-use systems, and after gamma irradiation of an assembled system, Thermo Fisher Scientific conducts verification testing that involves filling samples with tryptic soy broth (TSB) and exposure of the system to incubation for a two-week period. The sample system is determined to be sterile if no organism growth is detected. All sterile single-use systems that the company provides come with gamma sterilization certificates.
Need for standardization
One challenge for both integrators and their customers is the fragmented nature of the supplier base for single-use aseptic filling components. “As demand for single-use systems increases, growing numbers of vendors are entering into this market. Each single-use manufacturer has its own proprietary technology, and as a result there is a lack of standardization, which can be an issue on many levels,” Pence observes. “For end-users, it is critical that the industry strive toward a minimum level of standardization in order to mitigate risks associated with the use of single-use components from different suppliers while still providing systems that can be uniquely configured to a particular operation or application,” he continues. Standardization would also increase the efficiency of system development, and ultimately lower the cost of disposable aseptic filling systems.
“We believe that the key to increasing standardization will be the continued move toward greater automation in single-use aseptic filling systems. In the end, the choice to use, and thus the acceptance of, single-use systems comes down to performance, quality, and process economics,” remarks Hutchinson. “In parenteral manufacturing, there is a natural evolution toward more automated systems in order to ensure reduced risk of contamination and exposure of workers to highly potent drugs. Single-use systems are a natural fit for both automation and risk reduction. Therefore, these two complementary drivers will lead to implementation.”
Pence predicts strong growth for single-use aseptic filling systems over the next 5-10 years. “There is growing confidence in the use of disposable technology for upstream processing. As increasing numbers of people become comfortable with single-use systems and the awareness of the numerous benefits of this approach expands, more single-use aseptic-filling systems will be validated. In turn, confidence in these downstream systems will increase, and their adoption will spread.” He adds that the growing percentage of biopharmaceutical candidates (and thus parenteral drugs) will also drive interest in single-use systems throughout the parental production cycle, including aseptic fill–finish, as will continued pressure to further reduce contamination risks while increasing efficiencies and lowering costs.