The challenges of maintaining a contaminant-free fill-finish environment are numerous and complex, ranging from cleanroom maintenance to equipment sterilization to aseptic lyophilization and stoppering. These challenges grow in complexity as broad-base “blockbuster” drugs are ousted by targeted biologics that must be manufactured in small batches, demanding a high degree of flexibility in the manufacturing environment.
Forward-looking manufacturers are addressing these evolving complexities via a variety of innovative tools and technologies. For example, a growing number of facilities have replaced at least some of their conventional stainless steel fill-finish equipment with single-use instruments composed of disposable polymers. A significant number of manufacturers have also added the technology to aseptically fill syringes to maximize the yield of costly drug substance. And many have augmented their human capital with automated or semi-automated filling processes.
Although all three of these innovations have increased efficiency and flexibility at the fill-finish stage, they also introduce new risks into the process, and remain limited in their applicability. Thus, a manufacturer must carefully consider the cost-benefit tradeoff of adopting any of these novel techniques and tools. The following sections will examine the costs and benefits associated with each of these innovations in greater detail.
Part 2: Single-use systems, pre-filled syringes, and automated fill-finish systems.
Single-use systems simplify equipment sterilization and help lower production costs.
The benefits of single-use systems are clear: by replacing traditional stainless steel filling equipment with disposable parts made of plastic polymers, single-use instruments eliminate the need to sterilize components via expensive, time-consuming processes like autoclaving or dry heat circulation. This not only reduces the time required to perform sterilization procedures, but also lowers the requirements for water, as well as power for heat generation, to sterilize equipment between batches.
In addition, single-use instruments reduce the storage space necessary to perform many manufacturing processes because they tend to be far lighter and less bulky than their steel counterparts. This means more areas of the facility can be set aside for multiple simultaneous research or manufacturing projects, enabling staff to work on many more small batches in parallel, and enhancing flexibility for facilities working on many small batches of targeted biologics.
For the same reason, initial setup costs associated with single-use instruments also tend to be far lower than those involved in acquiring and transporting steel equipment. Single-use instruments can often be purchased at far lower costs than their stainless-steel counterparts, and can be shipped to the facility, or transported between facilities, more much rapidly, and in larger numbers. This further increases flexibility for manufacturers facing the demand to produce a variety of small-batch biologics at once, potentially at multiple facilities; or to rotate certain pieces of manufacturing equipment among facilities at certain times.
By reducing auxiliary costs in a wide variety of areas, from steam and heat to storage and sterilization, single-use fill-finish technologies help lower the investment involved in producing batches of biologic pharmaceuticals.
Pre-filled syringes eliminate the need for overfill, maximizing yield.
Just as some manufacturers are phasing out stainless steel equipment in favor of single-use polymeric instruments, an increasing number are also replacing traditional vials with pre-filled syringes. These syringes help minimize waste, by helping manufacturers avoid accidental overfill, or rendering batches of product ineffective or unsafe due to contamination. Instead of inserting a syringe into a vial to fill it with a dose, a technician or clinician can use a pre-sterilized syringe, which enhances safety and eliminates the need for repeated sterilization.
In addition, pre-filled syringes can be integrated into a manufacturing pipeline at any scale, from small-batch all the way up to full commercial production. This is particularly useful for manufacturers who need to feed many syringes through an electron beam sterilizer, or another sterilization instrument that performs best with a high throughput of drug containers. One key result is that pre-filled syringes of biologic product can be delivered to the endpoint more rapidly, and at a lower cost, than traditional syringes.
In all these ways, pre-filled syringes can help reduce human error, by limiting the need for manual contact with syringes. These benefits make pre-filled syringes a highly desirable technology for biologics manufacturers, who must package each dose with extreme precision, avoid overfill, and prevent contamination at every stage of the manufacturing, packaging, storage and delivery pipeline.
Automated fill-finish systems enhance efficiency, but limit small-batch flexibility.
The adoption of automation technologies into the fill-finish process presents many clear benefits, while also introducing its own restrictions on agile manufacturing. Automated equipment makes the fill-finish process consistent and endlessly repeatable, eliminating human error, and increasing the manufacturer’s ability to meet production quotas on tight deadlines.
By removing human operators from certain steps of the pipeline, automated fill-finish technologies also decrease the number of staff members required to complete a batch, reducing the overall cost of that batch, while also enhancing the flexibility of technicians, who can work on multiple small batches in the same facility.
At the same time, an automated fill-finish process can significantly increase the number of batches a facility is able to produce each day. Automated systems can complete each iteration of the fill-finish step far more rapidly than human operators can, without ever needing to stop for a break. As enhancements in machine learning improve the precision of these systems, they may become increasingly capable of addressing unexpected variations and accidents in the filling stage.
However, as the state of automated fill-finish technology stands today, programmatic filling offers little flexibility in comparison with human experts. Automated systems must be explicitly programmed to perform the fill-finish step in a particular way, and will persist in that behavior until instructed to perform a different process. While this might appear to be an advantage, it renders automated systems ill-equipped to respond to accidents and other unexpected variations in the fill-finish stage.
While these novel technologies and materials have streamlined manufacturing for many biopharma firms, the benefits of enhanced sterility, reduced error rates and lower margins come with their own unique costs. Biologic developers will need to partner ever more closely with their manufacturing partners to capitalize on these evolving processes, and gain efficiency and savings without sacrificing the quality of their products.
In Part 1 of this two-part series, we discuss why a growing number of biologic manufacturers are turning to new aseptic fill-finish technologies, including blow-fill-seal systems and single-use equipment.