The global market for biopharmaceuticals continues to grow at a rapid pace, with a 9.5% compound annual growth rate (CAGR) predicted over the next eight years. That translates into more than $500 billion in projected growth. So it is no surprise that biopharmaceutical manufacturers are investing heavily in new facilities, technologies, and pipelines for manufacturing drug products.
Even so, the need to prevent contamination places stringent handling and packaging requirements on biomanufacturers. Sterilizing equipment often requires steam autoclaves and dry heat, and even can include treatment by irradiation. In fact, the US Food and Drug Administration (FDA) mandates that all containers used in a sterile manufacturing process must be sterilized before contact with a drug product. The agency has recalled a number of pharmaceutical products for failing to comply with this requirement.
For those reasons, a growing number of biomanufacturers are turning to new aseptic fill–finish technologies, including blow–fill–seal systems and single-use equipment. Although such new technologies are being adopted increasingly, core demands of fill–finish processes remain the same: to keep equipment and formulations free from contamination and to package the product in a way that preserves the biochemical conditions that will be most conducive to the safety and efficacy of each biopharmaceutical product.
Here I provide a comprehensive overview of core considerations in fill– finish processes, along with insights into the improvements many manufacturers are making to address these challenges and answers to commonly asked questions in the “Q&A” box.
Design a Facility to Safeguard Aseptic Conditions
When designing a fill–finish process, the first consideration is the design of the facility in which the operation will be performed. An aseptic fill–finish system requires a cleanroom, and the maintenance of this aseptic environment requires far more than simply sterilizing equipment. A cleanroom’s air, for example, must be circulated through a high-efficiency particulate air (HEPA) filtration system. This airflow must be monitored for the presence of even minor amounts of contaminants that can jeopardize the sterility of an entire manufacturing pipeline.
The layout of a cleanroom must funnel workers and equipment from areas with the highest sterility toward those with the least. This type of layout prevents inadvertent contact of nonsterile tools with those that have been presterilized. A room’s layout must enable disposable components (e.g., stopper bowls and needles) to be replaced easily without disrupting the overall flow from sterile to less-sterile areas.
In a cleanroom, equipment or packaging materials using aluminum seals must be prevented from contacting equipment that can become contaminated by contact with aluminum. Stoppering equipment, in particular, must be kept separate from aluminum and other potential contaminants, and it should be placed as near to a lyophilizer as is feasible to keep the time from lyophilization to stoppering as brief as possible.
Sterilizing Techniques Must Be Appropriate for Formulation and Equipment
Before equipment or packaging can enter a cleanroom, it must be sterilized. Systems used to sterilize equipment must be chosen carefully, because each approach will have a different impact on different formulations and packaging materials and on various types of contaminants that may be present on equipment and tools used in a fill–finish process.
The most conventional sterilization technique is steam autoclaving, which effectively eliminates many pathogens. However, this method can degrade delicate components of a formulation, including amino acids, which are essential to biologic drugs. Steam autoclaving also can be detrimental to tools and packaging that are highly sensitive to heat and moisture. Still, this technique remains a trusted standby for sterilizing fill– finish equipment.
An alternative method is the use of dry-heat ovens, which can sterilize equipment in batches, or a tunnel that circulates extremely hot, dry air over bottles and other equipment. Although this technique prevents exposing fill– finish equipment to moisture, it still can damage heat-sensitive formulations or equipment made of materials that degrade under high temperatures.
A growing number of pharmaceutical manufacturers now are adopting radiation sterilization technology as a supplement to traditional techniques such as steam autoclaving. Ionizing radiation has been shown to kill many types of bacteria that survive heat sterilization, and gamma radiation achieves an even higher penetration and termination rate. When using radiation to sterilize fill–finish equipment, however, a manufacturer must consider the effect of irradiated particles on components of a formulation.
Manufacturing Must Be Performed Aseptically
Many biologics are lyophilized before bottling. A sterile fill–finish step adds additional constraints to the already numerous risks and challenges of lyophilization, thus requiring the design of a packaging pipeline that minimizes transfer time between a lyophilizer and vial or bottle filling.
Many manufacturers address this challenge with automated or semiautomated loading procedures in which a sterilized core is transferred directly into each vial without leaving a lyophilizer. This type of filling process requires an extraordinarily precise setup: Vials must be prepared in batches, with their stoppers resting on vial edges. Then vials are carefully loaded into a lyophilizer, where they undergo freezing along with drug formulation.
After the primary and secondary drying steps have been completed, a fully lyophilized drug is inserted automatically into vials, and the lyophilizer shelves are lowered, causing stoppers to attach to vials. Thus an aseptic fill–finish process is completed without ever removing a drug product from the lyophilization environment.
Specialized Biologics Manufacturers Are Adopting New Fill–Finish Technologies
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. Such cases demand great flexibility in a manufacturing environment.
Forward-looking manufacturers are addressing those evolving complexities by using innovative tools and technologies. For example, a growing number of facilities have replaced at least some conventional stainless steel fill–finish equipment with single-use instruments composed of disposable polymers. A significant number of manufacturers also have added technologies to fill syringes aseptically to maximize yields of costly drug substances. And many facilities have augmented their resources with automated or semiautomated filling processes.
Although all three of those innovations have increased efficiency and flexibility at the fill–finish stage, they also introduce new risks into a process and remain limited in their applicability. So a biomanufacturer must consider carefully the cost–benefit tradeoff of adopting novel techniques and tools. The following sections examine the costs and benefits associated with each innovations in detail.
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 with expensive, time-consuming processes such as autoclaving or dry-heat circulation. That not only reduces the time required to perform sterilization procedures, but it also lowers the requirements for water and power for heat generation to sterilize equipment between batches.
Single-use instruments reduce the storage space required to perform many manufacturing processes because they tend to be far lighter and less bulky than their steel counterparts. This means that more areas of a facility can be set aside for multiple simultaneous research or manufacturing projects, thus enabling staff to work on small batches in parallel and enhancing flexibility for facilities working on 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 often can be purchased at far lower costs than their stainless-steel counterparts, and they can be shipped to a facility or transported between facilities much more rapidly and in larger numbers than can stainless steel systems. That further increases flexibility for manufacturers facing demands to produce different 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 (e.g., from steam and heat to storage and sterilization), single-use fill-finish technologies help lower the investment involved in producing biopharmaceutical batches.
Just as some manufacturers are phasing out stainless steel equipment in favor of single-use polymeric instruments, an increasing number also are replacing traditional vials with prefilled syringes. These syringes help minimize waste by helping manufacturers prevent accidental overfill or rendering batches of product ineffective or unsafe because of contamination. Instead of inserting a syringe into a vial to fill it with a dose, a technician or clinician can use a presterilized syringe, thus enhancing safety and eliminating the need for repeated sterilization.
Prefilled 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 that need to feed many syringes through an electron beam sterilizer or other sterilization instrument that performs best with a high throughput of drug containers. One key result is that prefilled syringes of a drug product can be delivered to an endpoint more rapidly and at a lower cost than can traditional syringes.
Prefilled syringes can help reduce human error by limiting the need for manual contact with syringes. Such benefits make prefilled syringes a highly desirable technology for biomanufacturers that must package each dose with extreme precision, prevent overfill, and reduce risk of contamination at every stage of the manufacturing, packaging, storage, and delivery pipeline.
Adoption of automation technologies into a 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, thereby eliminating human error and increasing a manufacturer’s ability to meet production quotas on tight deadlines.
When human operators are removed from certain steps of a pipeline, automated fill–finish technologies decrease the number of staff members required to complete a batch. So overall costs per batch are reduced, and flexibility is enhanced for technicians who can work on multiple small batches in the same facility.
At the same time, an automated fill–finish process can increase significantly the number of batches a facility can produce each day. Automated systems can complete each iteration of a fill–finish step far more rapidly than can human operators — without ever needing to stop for a break. As enhancements in machine learning improve the precision of these systems, they can become increasingly capable of addressing unexpected variations and accidents during filling.
However, as the state of automated fill–finish technology stands today, programmatic filling offers little flexibility as comparison with such tasks conducted by human experts. Automated systems must be programmed explicitly to perform fill– finish steps in a particular way and must persist in that task until instructed to perform a different process. Although this might appear to be an advantage, it renders automated systems ill-equipped to respond to accidents and other unexpected variations in a fill–finish operation.
Although novel technologies and materials have streamlined manufacturing for many biopharmaceutical companies, the benefits of enhanced sterility, reduced error rates, and lower margins come with their own discrete costs. Biotherapy developers will need to partner ever more closely with their manufacturing partners to capitalize on such evolving processes and gain efficiency and savings without sacrificing product quality.
BJ Hull is vice president and general manager of Emergent BioSolutions, 1111 S. Paca Street, Baltimore, MD 21230; 1-410-843-5000.