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Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.
Innovation in manufacturing technologies must occur to ensure the availability of gene and cell therapies.
The rapid advance of gene and modified cell therapies and growing interest in viral vaccine therapies are creating significant demand for large-scale viral-vector manufacturing capabilities. Biopharma companies and contract manufacturers alike face a host of challenges as they work to meet this crucial market need, from a limited availability of technology to a lack of standardization to complex and evolving regulatory pathways.
There are numerous challenges to sourcing effective large-scale manufacturing solutions for viral vector production. Based on conversations with customers over the past several years, Univercells has identified the major hurdles in large-scale virus manufacture, which include expensive manufacturing facilities, lack of expertise, limitations in the number of scalable manufacturing technologies available in the market, and the high cost of good manufacturing practice (GMP)-grade reagents including transfection mix, plasmids, and bovine serum, according to Thomas Theelen, business development manager at the company.
“Equipment and facility setup using the technology that is available, most of which has been adapted from other therapeutic areas, is very expensive and often does not support product manufacture through different maturity stages including process development, clinical trials, and commercialization. In addition, the level of expertise around developing large-scale manufacturing processes for gene therapies is limited, and the use of flatware for cell culture and sub-optimal downstream processing protocols result in low yields; both factors also influence the overall cost of goods sold (COGS),” Theelen explains.
“Existing manufacturing processes are often complex with hard-to-control unit operations and unfavorable COGS profiles,” agrees Xin Swanson, head of commercial development for viral vector gene therapy, Lonza Pharma & Biotech. As an example, she points to the widely used transient transfection process for associated adeno virus and lentivirus (AAV and LV, respectively) production, which mainly uses adherent cells and lacks scalability and lot-to-lot consistency due to variability in transfection efficiencies. In addition, she notes that many downstream processes for early-stage clinical production often employ gradient centrifugation steps that lack the ability to be furthered scaled.
“Overall the volumetric productivity of virus particles per cell from culture systems and complete virus recovery rates through downstream processing are sub-optimal among existing production systems, both of which negatively impacts COGS. As a result, the lack of standardized production platforms that support industrialized scale processes is the leading challenge,” Swanson concludes.
Further complicating the situation is a lack of standardized and advanced analytical methods for vector characterization and release testing (including in-process samples), which makes it difficult to have well-understood manufacturing processes before incorporating process improvement steps, according to Swanson. Other challenges include a lack of automation in key steps of the manufacturing process; immature supply chains, which creates risk and leads to a lack of standardization/innovation of critical raw materials; and rapidly advancing regulatory pathways that are complex to manage among different jurisdictions.
Many of these challenges have existed for several years, with some developments occurring along the way. For instance, Theelen observes that novel scalable bioreactor systems, the implementation of continuous bioprocessing, and the introduction of new resins for viral vector purification are having an impact. “Several companies are developing suspension-based processes and implementing stable producer cell lines,” he notes. However, he adds that even though stable cell lines have the potential to significantly reduce COGS, developing robust processes using these stable cell lines is still a challenge. The same is true for suspension-based processes, which currently require significant investments in process development and extend the time to market.
What has largely changed, according to Swanson, is the timeline for overcoming these challenges. “It is critical to meet the clinical and commercial manufacturing needs for these curative therapies, and the need is becoming more urgent due to the rapid advance of clinical progress. The lack of manufacturing scalability has created a vector shortage, and the collection of sufficient vector chemistry, manufacturing, and controls (CMC) information has become a bottleneck during the product development lifecycle,” she asserts.
Theelen adds that to ensure that more gene and other next-generation therapies reach patients, reducing COGS is necessary to increase availability, facilitate reimbursement, alleviate the burden on healthcare budgets, and ensure that innovator companies can offer their products at an affordable price while maintaining sustainable gross margins. “Scalable and reliable technologies for cost-effective cell and gene therapy manufacture will reduce the reliance of biopharmaceutical companies on hard-to-acquire expertise and dependence on contract development and manufacturing organizations (CDMOs),” he says.
Additionally, Theelen notes that developing technologies that facilitate process and product development will shorten the time-to-market and reduce development costs, while increasing the number of technology candidates will intensify competition and finally drive down materials and equipment costs.
Technology innovation is key to addressing the challenges associated with large-scale GMP viral vector manufacturing, agrees Tania Pereira Chilima, NevoLine product manager at Univercells. “Solutions that are tailored for gene therapy manufacture and combine a low capital investment, scalability, ease-of-operation, and robustness while maintaining product quality are needed,” she comments.
It is also important that these technologies also are able to accommodate the manufacture of gene therapy products with low and high annual demands in order to ease the development and commercialization of personalized gene therapies and viral vector-based vaccines. Lowering the capital investment is also necessary for reducing the entry barriers for gene therapy start-up companies.
Swanson adds that all of the major challenges must be tackled concurrently in order to address the manufacturing challenges. “The optimal goal is to deliver products that will meet target product profiles with defined quality attributes while realizing the need to increase process productivity and reduce COGS,” she says.
CDMOs have a vital role to play when it comes to manufacturing innovation for viral vector production. “Given the fast pace of clinical development timelines and the unconventional demand curve of curative therapies, CDMOs offer competitive advantages not only from a manufacturing technology advancement perspective, but also from a cost perspective with respect to optimizing capital expenditures and better managing operating expenses,” Swanson states.
Pereira Chilima agrees that CDMOs are a major gateway for the adoption of new technologies. “Many established gene-therapy developers rely on CDMOs throughout all stages of product development and even once they reach the commercialization stage. The expertise of CDMOs in large-scale production helps cell therapy developers evaluate different avenues for cell therapy manufacture and select the technologies to be used once they decide to internalize product production,” she explains.
CDMOs are also in the unique position of developing and providing manufacturing platform processes that will allow drug developers to focus on product innovation and significantly shorten the gene-to-product development timeline, according to Swanson.
One of the most important developments highlighted by Swanson has been the transitioning of cell-culture processes from an adherent format to a suspensions format via cell-line adaptation, which is enabling better scalability. Development of stable producer cell lines is also reducing process variability and enabling the adoption of intensified processing solutions. A better understanding of the important qualities of critical raw materials, such as animal serum, plasmids, non-chemically-defined media, and the extractables/leachables associated with single-use technologies has also helped to address some manufacturing challenges.
Incorporating design-of-experiment study principles and use of improved bioprocess control and data analysis software are allowing process development/optimization to be conducted at the multiparameter level, while new analytical methods, such as more accurate viral vector quantitation techniques, provide a better understanding of impurity profiles and allow for better process monitoring. In downstream processing, density-gradient centrifugation is being replaced with chromatography methods for more consistent and efficient operations.
Collaboration between the different stakeholders in the industry is necessary to build on preexisting expertise and capitalize on academic innovation to help guide technology developers on the gaps that must be addressed in the industry, according to Pereira Chilima. Adds Swanson, “Collaboration between members of the value chain, ranging from innovators, manufacturers, and reagent and equipment suppliers to regulators, as well as close collaboration between academic and industry partners, is critical in driving solution development.”
Pereira Chilima also notes that involving the regulatory bodies and payers early on is needed to reduce regulatory barriers and ensure adequate reimbursement.
These types of collaborative efforts are ongoing, she says. Good examples include the efforts made by the Cell and Gene Therapy Catapult and Cobra Biologics to investigate continuous manufacturing. Univercells is also actively discussing promising collaborations with established gene therapy companies with the aim of combing its expertise to develop manufacturing solutions for end-to-end viral vector production for gene therapy applications.
Lonza has invested substantial internal research and development efforts in platform development, particularly in the area of AAV and LV production. Specific focus areas include scalable suspension-based transient transfection processes and stable producer cell-line technologies, according to Swanson. Concurrently, the company is investing in the development of novel analytical methods and new media formulations with the aim to provide turn-key solutions.
Separately, Lonza has invested heavily in a manufacturing capacity expansion with the opening of its dedicated, 300,000-sq.-ft. cell- and gene-therapy facility in Houston in 2018. The facility uses an extensive modular design concept and employs single-use technologies to allow clients quick access to scaled-up production capacity based on project needs.
Univercells, meanwhile, has developed the NevoLine platform, a modular and automated manufacturing system delivering affordable viral products such as vaccines and gene therapy vectors. This design of the NevoLine platform relies on a modular approach, allowing for a variety of configurations that provide tailored solutions for a range of products, according to Pereira Chilima. Viral-vector-specific NevoLine platforms can be designed for enabling AAV or LV manufacture for small- and large-scale applications.
At the core of the NevoLine platform lies the scale-X fixed-bed bioreactor coupled with in-line product concentration to intensify upstream processing and deliver large product quantities within a reduced footprint. “Intensification of each unit steps allows for drastic footprint reduction, enabling the entire process to be placed in self-contained modules such as isolators or biosafety cabinets,” Pereira Chilima explains. “The platform aims to minimize the capital investment for gene therapy manufacturers while delivering the low COGS and flexibility required to support the development and commercialization of gene therapy products, eventually ensuring their availability to patients,” she says.
Vol. 32, No. 9
When referring to this article, please cite it as C. Challener, “Seeking Solutions for Large-Scale GMP Viral Vector Manufacturing,"BioPharm International 32 (9) 2019.