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Drug efficacy, reputation, and financial return are all on the line when it comes to fill/finish.
When aseptic fill/finish is at center stage in biologics manufacturing, financial survival for the company and for the patient is (literally and figuratively) on the line. While monoclonal antibodies (mAbs) were the emergent class of therapeutic proteins in the past decade or two, the spotlight has shifted squarely onto cell and gene therapies, and an array of novel immunologically active agents. The challenge of biologic fragility, complexity, potency, and storage considerations have been mathematically “squared.” However, the rewards for both patients and companies are also rising in lock step, as “the global biologics market size reached US$321 billion in 2022. Looking forward, IMARC Group expects the market to reach US$535.5 billion by 2028, exhibiting a growth rate (CAGR) of 8.1% during 2023–2028” (1).
Extracted from, or produced through, living organisms, biologic therapeutics need special handling during every stage of the manufacturing process and distribution network. In complexity, even the older mAbs were likened to a commercial jetliner, simply because of the sheer number of tightly specified components requiring integration into the final complex product. An otherwise chaotic assemblage needs to be controlled, measured, monitored, and well maintained. Mitigating, and controlling for, at each step for a tendency toward degradation is the central framework. Principle factors to account for are unwanted cross-linking, inherent heat bloom caused by natural growth processes, peptide-bond hydrolysis, deamination, and so on. Care must also be taken to avoid overly concentrating protein solutions because much of the fill/finish success or failure hinges on flow rates. Adjustments are often made to avoid foaming, shear forces, and splashing, which tends to favor the use of peristaltic pumps over piston pumping systems. This method also reduces pressure (being gentler with inherently lower sheer forces) along with “easier cleaning and changeover because their disposable tubing, connectors, and filling needles are the only materials that directly contact the product” (2).
What is most important given the swift changes in types of therapeutics and also the technologies propelling them forward? A presentation by Rick Friedman, deputy director, Office of Manufacturing Quality, FDA/CDER Office of Compliance, emphasized robotic isolators. In his presentation Friedman said, the “use of robotics has potential to profoundly reduce quality and safety risks in aseptic processing. Of course, all technologies have failure modes, and appropriate design, control and maintenance practices are essential.” He added, “basic current good manufacturing practice (CGMP) provides the foundation for a transformational shift to robotics, where design still matters. There is a need to prevent disruption of first air; this includes ensuring size and speed of the arm does not adversely impact airflow.” (3). Overall, FDA appears very bullish on this technological innovation.
There are some trade-offs to the use of robotics in fill/finish to consider, however. Alaina Schlinker, Ph.D., Senior Manager of Field Application Support, ScaleReady, cautions, “there are situations where their use might not be ideal, due to substantial initial investment and setup costs. For cell and gene therapies in particular, validation, qualification, customization, and adaptation of robotic isolators can be time-consuming and require staff with highly specialized skills. Many in the field also have concerns about their lack of flexibility for rapidly evolving cell and gene therapy processes,” Schlinker concludes. However, despite these trade-offs, the clear trend toward adoption continues to accelerate as can be seen below.
The writing is on the wall for 20th century approaches, as Friedman points to a 2020 International Society for Pharmaceutical engineering (ISPE) survey on notable modernization trends, quoting a survey finding that, “The most notable outcome was the clear trend toward the use of barrier systems and the near extinction of ‘traditional’ cleanroom installations for aseptic filling. Respondents indicated that, in 2020, virtually no systems would be delivered without a form of RABS or isolator, illustrating that the industry is decidedly moving to the use of barrier systems. This is great news for patients and product safety.”
Because biologics are increasingly costly and low volume-based for many emerging therapeutics, it’s constructive to examine what steps are being taken to minimize loss of product while also increasing speed and throughput in the fill/finish stage. Kathie Schneider, director, Global Commercial Lead, Cell Therapy Technologies, at Terumo, states, “The largest risks that customers need to manage in the final manufacturing step of fill and finish is [to] limit any risk of contamination, and ensure that processing time is efficient. Dimethyl sulfoxide (DMSO) is the current gold standard for cryostorage. With accepted formulations for the GMP environment, its inherent toxicity has necessitated observation of minimal contact times, stage of introduction, and removal/wash steps. Hand in hand with this has been to need to document steps for the overall process. While these steps, when controlled and documented, have aided, there has also been a concomitant drive for DMSO free solutions.”In general, industry wide, there are growing calls for such avoidance, or often recycling of solvents, and there is potential environmental-based legislation affecting closely related chemical synthesized therapy solvents, such as acetonitrile in oligonucleotide synthesis in messenger RNA (mRNA) production, and many others. Schlinker points to adoption of closed and automated systems, single-use technologies, process intensification, and advanced analytics to address speed and efficiency bottlenecks. She also believes another key “cross-industry collaboration, which is already at work, [is] to standardize protocols. As innovators in this domain, ScaleReady remains dedicated to advancing these solutions.”
Anand Srinivasan, MS, PhD, executive director, Center for Innovations and Biodesign, Research and Development, BioBridge Global, points out that for cell therapy especially, “there remains a need for ‘miniaturized assays’ to use the small volume of residual product trapped in the tubing, bag, or filters for in-process testing. In the autologous market in particular, there is big push for minimal editing/engineering with less than 24-hour manufacturing time. These measures should be supported with innovations in potency assays, rapid assays for release testing, and logistics with traceability. For allogeneic therapies, the emphasis is not on the manufacturing time, but rather on the unit operations and reliable sensors.”
Srinivasan goes on to conjecture that, “Although automation is hailed as a cure for many obstacles in the space, it may not be necessary for all manufacturing processes and associated analytics. Counterintuitively, it might just increase the cost of goods for small-scale manufacturing process.” But this is currently a somewhat contrarian view. It’s hard to look away from the cell shuttle of Cellares, which calls itself the first Integrated Development and Manufacturing Organization (IDMO), “taking an Industry 4.0 approach to mass manufacturing the living drugs of the 21st century … an entire manufacturing process in a flexible and high-throughput platform that delivers true walk-away, end-to-end automation” (4).
While Thomas Heathman, VP of Commercial Operations, Ori Biotech, clearly agrees, emphasizing, “These are living therapies with real risks of cross-contamination, and the end stages of manufacturing can introduce a variety of factors that can threaten product sterility, viability, and potency. This is especially true for autologous therapies, where product sampling is required for every single batch produced and a variety of final product containers are used, such as bags and vials. These can go back to the patient directly or, more typically, be cryopreserved to extend product shelf-life and reduce the logistical burden of returning the product for administration.” Heathman goes on to add that, “By automating closed systems, coupled with digital solutions that can track and trace product from final formulation back the patient for administration, we will enable workflows that can help mitigate these risks and enable patient access to cell therapy products at scale.”
In its Horizons Life Science report, CRB points out that sterile filtration, a well-established tool in drug substance manufacturing, could “unlock huge advantages for gene therapy manufacturers such as smaller and more efficient facilities, lower operating costs, and opportunities for process closure. There’s a significant potential drawback, though: lentiviral and retroviral vectors typically sustain significant yield loss when exposed to a sterile filter” (5).
Natalia Elizalde, PhD, chief business development officer, VIVEbiotech, which specializes in lentiviral vectors, expounds on this point, saying, “Lentiviral vectors are very sensitive to various elements such as pH, temperature, shear forces, and chemical composition—specifically salt. They must be handled very carefully at the time of fill/finish.” She goes on to add, “Performing fill/finish in-house allows us to freeze the vectors as soon as their production is finished; this avoids additional freeze/thaw cycles caused by having to send the final product to an external CDMO to perform this. Moreover, the fact of freezing the lentiviruses in a row has a direct impact on the cost-effectiveness of
the whole process.”
The time and expense that is needed to train and retain operators, and then to re-train them again when increasing molecular diversity for a new therapeutic requires the process to begin anew, is a commonly heard challenge. Christa Myers, senior fellow, Aseptic & Sterile Products, CRB, relates, “There is a lot to learn and be able to speak to within this highly technical side of the industry. Character and personality matter. An operator needs to be able to follow protocols for manufacturing of a quality product. Each also needs to be able to think in a quality improvement mindset in order to plan for corrective actions and preventative actions (CAPAs). Your operators are your most valuable asset and should be trained and treated as such … it is very difficult to retain good staff. There has been a lot of growth and changes, salaries, benefits packages, and growth opportunities are drawing away strong trained operators. The training costs are not small and so keeping operators happy and at your company is important and less expensive than bringing in new staff. These costs are driving the need for automation to increase.”
As a natural consequence, many companies are working to reduce operators with more extensive automation. Myers continues, “The education backgrounds of operations staff are continuing to change. Many are now recruiting from mechatronics programs in community colleges or universities in order to hire operations staff that are well versed in equipment maintenance, robotics, automation, and mechanical systems.”And just as staff need to be constantly updated and refreshed, so too does the machinery itself.“Many think that they can install a fill line and it will easily operate for the next 20 years. A fill line is a complex mix of mechanical parts and automation. In order to manage the lifecycle of the machine, each sensor, each piece of hardware, and each software system needs to be maintained to a point so that the machine does not become obsolete. A strong life cycle management plan will allow the machine to grow older gracefully and not be obsolete quickly,” she concludes.
Jack Wright, vice president Sales & Marketing, Jubilant HollisterStier (JHS), sees equipment growth as integral to industry growth, commenting, “In terms of equipment upgrades, we see that as an important part of growing with the industry and being capable of approaching diverse and complex formulations with confidence. JHS has made significant infrastructure investments—in facilities and equipment—at our Spokane (Wash.) and Montreal locations. Some of these investments were made in particular to expand critical domestic vaccine manufacturing capacity.” And there are digital innovations infiltrating from other spheres of activity. We all became aware of Corning’s newly created Valor glass vials, while a totally new dimension is being pioneered by the company SmartSkin Technologies, offering sensor-enabled containers that measure the damaging forces across pharmaceutical and beverage manufacturing lines. Each biologic product has its own idiosyncrasies and, therefore, requires a fill/finish line in synch with those variables and characteristics. Automation does seem to offer a way out of some of the human errors and inherent inconsistencies, but there does seem to be a price to pay in terms of resource allocation, planning, and system-wide reeducation in how the remainder of the workforce’s role surrounding that automation. Automation therefore is not an unalloyed triumph, but another permutation in an ever-changing manufacturing landscape. The stakes are very high at the fill/finish line, and the benefits of getting things right here, speak volumes about the rest of the products journey.
Chris Spivey is the editorial director of BioPharm International.
Volume 36, No.10
When referring to this article, please cite it as Spivey, C. Hi-Fidelity Fill/Finish for Biologics. BioPharm International 36 (10) 2023 10-12.