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Both demand for and investment in fill/finish capacity continue to rise.
The biopharmaceutical pipeline is changing with respect to the diversity of modalities and delivery technologies while it is also expanding. This evolution has placed pressure on fill/finish capacity and capabilities across the sector. These challenges continue to be exacerbated by the COVID-19 pandemic, which has also highlighted supply-chain and cold-chain issues. Investments in both additional capacity and new equipment are improving the situation, but demand growth is expected to outpace these activities, at least into the near future.
The number of conventional monoclonal antibodies in the clinical pipeline remains high, even at a time when many new modalities—multispecifics, antibody conjugates, fusion proteins, and other next-generation antibody-based products; cell and gene therapies; nucleic acid-based treatments—and other novel entities are progressing from early to later development stages. There are also well more than 100 COVID-19 vaccines in clinical development, the vast majority of which are administered via injection and thus require aseptic fill/finish processing.
“Continued innovation in both conventional and next-generation protein therapeutics, cell and gene therapies, RNA- and DNA-based treatments, and vaccine technologies is driving demand for fill/finish capacity,” says Ping-Yang Yeh, president of AltruBio Taiwan, a subsidiary of AltruBio, Inc. He notes that the increase in demand for fill/finish capabilities just to meet the production needs for COVID-19 vaccines alone could account for the majority of existing capacity and thus potentially render a slowdown of clinical development and commercialization for other biotherapeutic candidates.
The increased demand for fill/finish operations is presenting scheduling challenges and requiring the need for better planning and more accurate demand forecasting, agrees Fred Fleitz, group vice president, chemistry, manufacturing and controls at Arrowhead Pharmaceuticals
The greater diversity of biologic modalities is creating some challenges with respect to fill/finish processes, according to Yeh. “Many of these biotherapeutics are unstable at room temperature and therefore require rapid fill/finish processing and delivery to the clinic. They also often are targeted therapies and thus more potent and produced in smaller batch sizes. Addressing both of these issues requires high agility and speed in fill/finish operations,” he observes.
Changes in efficiency and productivity during manufacturing operations are, agrees Kelly Christiansen, vice president and general manager of Emergent CDMO’s Rockville manufacturing facility, being largely driven by the growth of novel therapeutics and vaccines for rare and orphan indications, as well as new drug formulations that require technological advancements and flexible solutions for manufacturing.
Christiansen points specifically to the need for expertise in complex molecule formulation to help overcome challenges with stability and efficacy, including experience working with traditional liquid and lyophilized formulations as well as more complex bioconjugates, liposomes, and nanoparticle formulations. He adds that having the right equipment in place to ensure manufacturing needs are met for these novel modalities can be challenging.
One example highlighted by Yeh is the growing need for lyophilization capabilities, given the potential for freeze-drying to help overcome stability issues while enabling storage within the conventional cold-chain infrastructure (e.g., 2–8 oC vs -20–70 oC). “An increase in capacity for lyophilization fill/finish manufacturing and greater versatility in pharmaceutical container selection are needed,” he says.
The need to manage complex formulations and particularly high-viscosity products is another growing issue that is affecting fill/finish operations. High-concentration protein formulation has become a key enabler for patient self-administration for chronic disease indications. However, efforts to develop highly concentrated biologics for subcutaneous delivery can often result in viscosities at the edge of what peristaltic pumps can manage, according to Christy Eatmon, an R&D staff scientist in the Pharma Services group of Thermo Fisher Scientific.
“Care needs to be taken to handle these highly concentrated antibodies so that aggregation does not occur,” Eatmon comments. Yeh also remarks that fill/finish manufacturers should focus on the design of processes and equipment specifically for viscous biologics solutions so that line wastage can be reduced and recovery improved for these often-expensive drug substances.
Special handling or filling modifications may also be required for suspensions and dispersions to ensure homogeneity, Eatmon comments. Yeh agrees that the nature of vaccine and therapeutic modalities will determine facility design needs, including processes and components of choice.
As an example, Yeh mentions messenger RNA (mRNA) vaccines formulated as lipid nanoparticles (LNPs), which are unlike standard protein therapeutics that are typically soluble in aqueous formulations. In addition to continued need around the world for mRNA vaccines and boosters against the initial and newer variants of the SARS-CoV-2 virus, the success of the first two COVID-19 mRNA vaccines has driven interest in the use of these platforms for additional indications, observes Eatmon.
The discrepancy between mRNA and protein therapeutic formulations could impact the design of processing steps and the choice of equipment for manufacturing, while the greater instability of mRNA vaccines may reduce the time allowable for fill/finish operations to minimize room temperature exposure, according to Yeh. In fact, as more complex processes become the standard, process design and development of suites that allow for emulsion/dispersion technology will be required, according to Eatmon.
The constraints associated with mRNA products and other similar types of formulations, therefore, pose additional operational complexities in facility and logistics design and require additional resources compared to those needed for the standard processing of protein therapeutics, Yeh concludes.
In a similar vein, Eatmon notes that with the emergence of more intravitreal products, development of solutions for the delivery of small fill volumes in the range of 0.15–0.25 mL will be increasingly important.
Finally, with such a growing diversity of biologic modalities, manufacturers are faced with a shortage of qualified technical experts to support fill/finish operations from the process engineering, quality assurance and quality control, and regulatory perspective, according to Yeh. “Talent recruitment and retention, including rigorous training programs, will become crucial for fill/finish manufacturers that wish to stay competitive,” he contends.
The wider range of modalities is not the only change affecting fill/finish operations. There is also a shift in the industry towards single-use delivery systems (also considered ready-to-use containers) such as pre-filled syringes (PFS) and single-dose vials (SDVs), according to Sophia Percival, director of drug product manufacturing for Catalent.
For COVID-19 vaccines, multi-dose vials were used so that more people could be treated in the shortest amount of time. At this later point in the pandemic, however, companies are now considering ways to optimize resources and make delivery of treatments more patient- and carer-friendly. “PFSs and SDVs help ensure the correct dosing of patients and can also significantly reduce drug product waste,” Percival says. Patient and caregiver safety, including avoiding needlestick injury to those administering vaccines and treatments and disposing of spent needles, remain key drivers, she adds. Direct-to-patient delivery and home care are also made easier with PFSs and SDVs.
Eatmon agrees: “One of the biggest drivers in the movement to pre-filled syringes is the desire to make products easier to use. Whether that’s in
emergency medicine or at home by patients, there is an increasing desire
for efficiency and ease in delivery of parenteral medicines.”
Of course, as more products move from vials to syringes (and cartridges), the need for syringe capacity is growing.
The COVID-19 pandemic affected all business around the world, including the biopharmaceutical industry and fill/finish activities. It had, says Belinda Holdsworth, senior director, strategic growth project lead, Lonza Drug Product Services, a dramatic impact across the globe with almost no region left unaffected, and magnified the challenges of unpredictable demand and demand fluctuations. Specifically, it triggered the rapid development of vaccines, antivirals, antibody therapies, and diagnostic products, which in turn resulted in significant and rapid capacity ramp-up and, in the fill/finish sector, technological growth to support analytics and agile fill/finish capabilities.
At the same time, Holdsworth believes the pandemic drove biopharma companies to assess their manufacturing networks and supply chains, particularly in the scope of resilience. “This includes securing supply chains through dual source manufacturing and raw material suppliers, on-shoring of manufacturing, and response to personnel disruptions,” she explains.
Indeed, according to Percival, the COVID-19 pandemic brought about a significant and permanent change in the way that the pharmaceutical industry approaches the supply chain. “We are now more attuned to how materials are sourced globally, and how small changes to production in one part of the world can significantly limit the supply of critical materials,” she says.
In fact, Fleitz notes that the COVID-19 pandemic continues to present supply-chain issues, particularly for the supply of glass vials, caps, and seals, as well as with respect to the ability to achieve reliable, timely shipping of goods.
Percival also observes that the pandemic reminded manufacturers about the benefits of more traditional production methods, including reusable tanks and equipment that allow for more internal control and less reliance on the global supply chain for materials consumed during processing.
Impacts of the pandemic continue even though the virus is slowly becoming endemic. “I believe the COVID-19 pandemic will continue to apply stress to the fill/finish sector due to the high demand for manufacturing capacity and raw material supply,” Yeh comments.
Shortages do still continue to plague manufactures and range for single-use components such as bags and filters to primary packaging components, including vials, PFSs, and cartridges. Access to dependable shipping remains an issue as well.
“To address these challenges,” says Eatmon, “efforts are ongoing with suppliers and customers to account for long lead times and also look for alternatives that can be considered equivalent and will have minimal impact to the product validation and regulatory strategy.”
It is also imperative that fill/finish manufacturers keep a close watch on the quality of incoming raw materials. “Proactive raw-material-supplier management is imperative, particularly when a raw-material supplier makes changes to a process that may have inadvertent negative impacts on product quality,” Yeh states. “A thorough risk assessment on the adjacency of the raw material to the safety and efficacy of the product can help to manage the priority,” he adds. “In the meantime,” Yeh continues, “capability in forensic sciences and analysis should be established via the science-based approach to defend the decision on the disposition of batches, particularly when it comes to raw-material impacts.”
Yeh in particular points to issues with the supply of single-use system (SUS) components, for which lead times can be as long as 12 months. He does note that suppliers have been ramping up production through scale-up of existing processes and the building of additional manufacturing plants. However, he cautions that rapid expansion has in some cases resulted in compromised quality for some components depending on the process used to produce them and the particular manufacturing sites where they are made. These issues have, in turn, led to a higher incidence rate for manufacturing deviations and product lot rejections, according to Yeh.
Although there has been some recognition of the value that permanent stainless-steel manufacturing equipment can provide in times of supply shortages, the interest in disposable technologies for biologics manufacturing at commercial scale, including fill/finish operations, continues to grow.
“Industry competition continues to drive the need for improved efficiencies, lower costs, higher quality, safety, and regulatory compliance, and greater manufacturing agility. In response to these demands, the use of [SUS] continues to grow, as single-use technologies have proven to reduce overall facility costs while providing faster changeover times and lowering cross-contamination risk,” explains Holdsworth. The COVID-19 pandemic accelerated this trend.
Another related trend in biomanufacturing, according to Yeh, is the shift towards agile, modular design. “This new approach enables the reduction of facility footprints, speeds of the design-build-validation process, supports smaller batch sizes, and like SUS, reduced change-over times. All of these features are advantageous for novel biologic modalities, such as antibody-drug conjugates, bispecific antibodies, mRNA vaccines and therapeutics, and personalize medicines,” he comments.
Given the need for aseptic processing, the industry has been moving towards the use of closed processing solutions for many fill/finish operations. This trend is in alignment with the greater adoption of single-use technologies, and these systems provide better control over aseptic filling and thus greater sterility assurance, according to Fleitz.
“Gloveless, closed systems with robotic handling, filling, and closure processes provide a high level of sterility and fill accuracy and are ideal for supporting high-value, small-batch-size drug products such as next-generation therapies,” observes Christiansen.
Christiansen has seen the shift away from restricted access barrier systems (RABS) toward isolator systems in combination with increasing use of automation to streamline fill/finish operations. Isolator lines provide the flexibility for both large-scale therapeutic filling and enable smaller fill quantities for more targeted and potent products. Certain products (e.g., viral therapies), he notes, require the use of isolator technology.
“Isolators represent the superior choice in terms of sterility and eliminate more contamination risks, especially when combined with room controls such as biosafety
level 2 environments,” Christiansen states. In addition, such fill lines with integrated lyophilization capabilities minimize operator interventions and ensure aseptic conditions from fill to freeze drying.
Furthermore, isolators allow campaign filling, in which manufacturers fill one batch after the next without any intervening vaporous hydrogen peroxide cleaning cycles, which is an optimal approach for late-phase and commercial products that are produced in larger volumes.
One of the most significant trends in the fill/finish sector is the rapid growth of the contract development and manufacturing organization (CDMO) market, according to Holdsworth. Grand View Research predicts the sector will expand at a compound annual growth rate of 6.1% to reach $14.0 billion by 2030 (1). “An increasing number of new drug approvals are being filed by small and medium-sized pharma and biotech companies with no in-house manufacturing capabilities. CDMOs are strengthening their services across the full lifecycle, including product development, clinical testing, commercial manufacturing, and regulatory expertise, supporting this industry segment,” she says.
The COVID-19 pandemic only reinforced the pre-existing trend toward outsourcing. One fundamental change has been a shift to engagement by drug makers in strategic partnerships with the contract manufacturers they include in their established manufacturing networks. “Fill/finish vendors are becoming more of an integrated partner with our operations team, increasing the level of communication between us and vendors,” Fleitz notes.
Eatmon agrees that the role of the CDMO is changing. Rather than just provide one or two services that are predefined, partnerships are being formed in which both the CDMO and customer work together to come up with creative solutions for quality products. She points to the increased demand for pre-filled syringes as an important driver. “For PFSs, there is not only a need to fill the drug product, there is an increased demand for devices such as autoinjectors, necessitating engineering teams on both sides to come together and work on selecting the best device for the application.”
This more strategic approach, says Holdsworth, will facilitate regionalization, with manufacturing capabilities established around the world in countries where manufacturing was traditionally not strong. “This CDMO growth will bring much sought-after resilience to the market, facilitating expedited time-to-market and improving cost efficiencies,” she contends.
It is also helping some drug makers better manage the currently heavily constrained pharmaceutical supply chain, according to Percival. “Sponsor companies are relying more heavily on their outsourcing partners, requiring them to diversify their supply chains and assure reliable supply,” she notes.
Finding good-fit CDMOs is essential, though, Yeh emphasizes, particularly for small and virtual biotech companies, which constitute a significant segment of the biopharma industry. “While the general considerations of a competitive cost-structure and capacity are important, smaller companies also tend to value other differentiation factors too, including skill set, regulatory experiences, proven regulatory inspection record, operational agility, technical innovation, and ability to support projects from start to finish,” he says.
In fact, Yeh believes it is becoming increasingly important and highly desirable for CDMOs to provide support for development and manufacturing of both biologic drug substances and drug products through fill/finish, product inspection, labeling, and packaging “under the same roof”. “The fill/finish service can then be offered as a
continuation of the drug substance manufacturing service and be subjected to the same quality framework. Logistics, planning and procurement can also be streamlined to gain consistency and efficiency,” he explains.
With more combination products moving through the pipeline, such as PFSs that require autoinjectors, Yeh adds that the ability to streamline operations and logistics will become a key differentiating factor. Fleitz notes, too, that “end-to-end” CDMOs with the flexibility to support filling of both small batches for early-phase clinical programs and larger-volume filling within to meet Phase III and commercial needs will be in demand.
Manufacturers are not completely alone as they work to meet evolving fill/finish needs. Equipment vendors are aware of the key shifts in the sector, and some have already expended significant effort to introduce new solutions. Yeh points to new types of aseptic filling systems that integrate technologies applicable for ready-to-use pharmaceutical glass containers and isolator systems that comprise modular processing units with built-in robotic capabilities. “Such new equipment offers the advantages of a smaller manufacturing footprint, shorter design-build-validation times, and minimization of human interventions during operations. They also provide the flexibility needed to manage the ever-increasing demand for fill/finish capacity and provide an effective way to generate process insights through efficient data collection and analysis,” he believes.
The need to produce millions of doses of COVID-19 vaccines led to a huge surge in fill/finish infrastructure investment, according to Holdsworth. She stresses that this high level of capacity expansion remains strong and sustained. “Even so,” she adds, “global capacity remains insufficient, and ongoing infrastructure investment, particularly by CDMOs, is needed to ease this gap.”
Christiansen notes that the continuing significant investment is largely in isolator-based technology “because of the flexibility it offers for aseptic filling, processing both vials and syringes, and the enhanced sterility assurance made possible through minimized operator interventions and automation.” Emergent CDMO has, for instance, proactively invested more than $150 million in capability expansions across multiple sites to provide additional drug-product manufacturing automation and capacity, including isolator technology, inspection, and packaging and labeling lines.
Eatmon, meanwhile, underscores the fact that investments are not just needed to expand fill/finish capacity. “Significant funding also must be directed towards increasing the capacity for inspection, packaging, and other supporting activities,” she states.
Despite the challenges posed in recent years for fill/finish operations, there are high expectations that investments in innovation and capacity will help move the field forward significantly. “Aseptic fill/finish continues to be a dynamic and exciting area of the pharmaceutical industry,” avers Eatmon. Yeh adds that although the focus in the biopharma industry has traditionally been on drug substance manufacturing, the sector has matured to the point where platform technologies are now widely used. He believes that “the time has come for the focus to shift to drug product manufacturing, with an emphasis on fill/finish, as it is a key enabler for product differentiation.”
Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.
Volume 35, Number 10
When referring to this article, please cite it as C.A. Challener, “Focus on Fill and Finish,” BioPharm International 35 (10) (2022).