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Precompetitive consortiums seek solutions to industry-wide challenges.
Precompetitive consortiums create a space for both manufacturers and equipment and technology suppliers to find solutions to manufacturing challenges that affect the whole industry. By working together, they seek to create standardized tools—including software, hardware, and analytical methods—and to harmonize the technical language around these tools. One of the desired results is that vendors can then create products that all manufacturers can use, rather than designing bespoke solutions. Another way consortiums boost technology adoption is by bringing together different perspectives to identify industry challenges, broaden and clarify the definition of specific problems, and propose “roadmaps” that companies can then use in their own journeys.
“A consortia-based approach affords the opportunity to broadly advance capabilities that can be used by many—and do so more quickly—through more iterations being conducted and communicated in a more compressed timeframe,” explains Chris Yochim, business development director at the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) in the United States. “Individual companies must intensely focus on addressing the challenges of their respective product portfolios. They try to apply what they learn to the next product coming through, but they are limited by whatever experiences they did or didn’t happen to encounter.”
Consortiums are especially crucial for emerging therapy areas. As these therapies move through development toward commercialization, collaborative efforts can help speed the solution of problems that arise when trying to manufacture efficiently at commercial scale. The common goal is to bring solutions—quickly and cost-effectively—to patients. Many companies and organizations, including consortiums, are currently working on challenges related to improving the manufacturing processes of cell and gene therapies (CGTs) as well as those of viral vectors, which are crucial raw materials.
“[Cell and gene therapies] are incredibly complex by historical biopharma industry standards,” says Tim Charlebois, NIIMBL Senior Fellow. “While we have seen great promise with the early successes, there is still a lot we don’t understand about them—how to make them, how to analyze them, [and] how to ensure they can be produced with a reliability and quality that meet the standards that patients expect and deserve. At the same time, there is great urgency to develop products rapidly, because many of the therapies are intended to address acute unmet medical needs.”
Charlebois explains that one challenge is understanding the relationship of critical quality attributes to fundamental process and analytical technology. Other challenges involve workforce needs and manufacturing capacity, complexity, and cost. “Overall, these challenges are tied to the tremendous novelty and diversity of the candidate technologies and therapeutic approaches being undertaken,” he concludes.
BioPhorum’s Cell and Gene Therapy Phorum, formed in 2018, aims to facilitate development of CGTs and smooth the way to commercialization of CGT products (1). For example, detailed process maps for the manufacture of cell therapies (2) and gene therapies (3) explain the different modalities. A “toolkit” released by BioPhorum in April 2022 (4) defines and describes the complex ecosystems of CGT manufacturing and supply to “provide a common language and framework for collaboration,” (5) which is important for supply partnerships and, in particular, for developing information technology (IT) systems. BioPhorum says that the models, which map out six common types of CGTs, can be expanded to new modalities as needed. According to BioPhorum, “If IT solutions built today can support multiple therapy modalities, then future therapies can be brought to market more quickly and supported more easily” (6).
The Bio-Process Systems Alliance (BPSA), an industry association that facilitates biopharmaceutical manufacturing using single-use technologies (SUT), has a technical committee dedicated to CGT chaired by Brendan Lucey, who is also Cross Unit director of Marketing Strategy at Entegris.
“Due to the broad nature of our membership, we are able to understand what is going on across the industry and address the pain points that we are seeing globally,” says Lucey. He says that a key advantage of addressing these issues through the BPSA consortium is having input from both the end users (i.e., drug manufacturers) and the SUT suppliers to find solutions that will work for everyone. Having broad solutions, rather than a custom solution that works for just one user, has been crucial to meet production needs during times of tight global supply chains, such as those the industry has been experiencing in the past couple years.
Increasing the industry’s capacity to make and supply viral vectors has been of high importance, as demand for these starting materials in cell and gene therapy production has outpaced supply. The BPSA CGT Committee has been working on a technical guide for viral vector manufacturing, which is due to be published in June 2022.
“This paper was an 18-month project led by more than a dozen subject matter experts [who have] insights into the challenges and benefits of scalable cell and gene therapy processes,” says Kevin Ott, executive director of BPSA.
The report will discuss how SUT can meet both present and future challenges in viral vector manufacturing. It will address topics including scalability, standardization, change management, system robustness and integrity, and quality. The paper will also show how a completely closed system is designed to keep out any potential contaminants, says Lucey.
The committee has previously published technical guides detailing best practices for SUT in CGT manufacturing (7) and considerations for extractables and leachables (E&L) in CGT development (8).
“Each emerging biotherapeutic class comes with potentially unique process, regulatory, and commercial requirements that must be taken into account,” says Lucey. For example, E&L concerns in CGT differ from the historical concerns of other types of bioprocessing. “[The BPSA report on CGT E&L considerations] helps end users assess their risk and think about regulatory concerns before having that first meeting with regulatory agencies. It enables end users to make smart choices early in the process that reduce any E&L concerns,” he explains.
NIIMBL, a public-private partnership funded by the US federal government and consortium members, works to advance biopharmaceutical
manufacturing in the US through activities such as developing standards and workforce training. In the CGT area, NIIMBL is focusing on viral vector manufacturing and analytics.
“Limited availability of viral vectors, such as adeno-associated virus (AAV) and lentivirus, represent a major bottleneck, which is constraining the growth and successful development of both gene and cell therapies,” says Charlebois. “Enormous investments in facilities, equipment, technology, and staff have recently been undertaken, but there is a long way to go to meet the overall needs of the cell and gene therapy community. We are bringing together thought leaders and technical experts across industry to develop a program of collaborative, precompetitive work that can both advance and improve access to the critical process and analytical technologies in this space. We are also developing and supporting workforce programs to help address the rapidly growing need for expertise in technical development, manufacturing, quality, and regulatory disciplines for viral vector manufacturing.”
In one project, the United States Pharmacopeia and the US Department of Commerce’s National Institute of Standards and Technology are performing an interlaboratory study to measure critical quality attributes for AAV products, which can be used to deliver gene therapies, and NIIMBL is providing the collaborative platform (9).
In a project funded through the American Rescue Plan (10), Caring Cross is working with NIIMBL to develop open-source platform technologies and materials for AAV and lentivirus. “The intent is to make these broadly available for research purposes and enhance the ability of investigators and smaller, less-well funded entities to pursue therapies dependent on viral vectors,” explains Charlebois.
NIIMBL is also partnering with the international advocacy group Alliance for Regenerative Medicine (ARM). NIIMBL and ARM’s Project A-Gene is a case study-based approach to integrating quality-by-design (QbD) principles in gene therapy chemistry, manufacturing, and controls programs (11). The project brought together more than 50 industry experts from 20 therapeutic developers, as well as experts from FDA and the Standards Coordinating Body for Gene, Cell, and Regenerative Medicines and Cell-Based Drug Discovery to identify best practices for the manufacture of a viral vector for use in gene therapy. The results of the four-year project were shared in a report (12) and in a webinar series that will culminate with a workshop in June 2022. The project leaders hope that the study will help developers overcome barriers to moving from clinical trials to commercial production, similarly to how a 2009 case study on applying QbD to monoclonal antibody production lowered barriers in that area (11).
“The case study represents current thinking around best practices in advancing small-batch clinical trial manufacturing to commercial-scale production,” explains Gene Schaefer, NIIMBL Senior Fellow. “The output document is a valuable reference for both organizations that participated as well as other organizations working in this area. [The document] is not meant to be prescriptive, but rather a starting point for discussions and decisions within an organization about the best approach that aligns with an organization’s capabilities and priorities.”
Later in 2022, ARM and NIIMBL will be releasing project A-Cell, which takes a similar approach of applying QbD principles to the manufacture of a cell-based therapy.
Companies should get involved in consortia that are relevant to them, both to benefit themselves and the industry as a whole. “Progress is being made to advance the field, and that progress benefits from as broad a cross-section of stakeholders being engaged as possible,” concludes Yochim. “Organizations that actively engage in meetings, on project teams, in the governance of the institute, and in other ways generally have very deep and lasting interactions that provide technical and workforce-related benefits back to the member.”
1. BioPhorum, “Cell and Gene Therapy,” biophorum.com, accessed April 26, 2022.
2. BioPhorum, “Commercialization: Cell Therapy Process Map,” biophorum.com (September 2020).
3. BioPhorum, “Commercialization: Gene Therapy Process Map,” biophorum.com (September 2020).
4. BioPhorum, “IT for Cell and Gene Therapies,” biophorum.com, accessed April 26, 2022.
5. BioPhorum, “Orchestrating the Supply of Different Cell and Gene Therapies,” biophorum.com (April 4, 2022).
6. BioPhorum, “CGT Actors and Process Maps: Who Does What in the Supply of Different Cell and Gene Therapies,” biophorum.com (April 1, 2022).
7. BPSA, “The Role of Single-Use Polymeric Solutions in Enabling Cell and Gene Therapy Production,” bpsalliance.org (2019).
8. BPSA, “Extractables/Leachables Considerations for Cell & Gene Therapy Drug Product Development,” bpsalliance.org (2020).
9. NIIMBL, “New Collaboration Aims to Improve Measurement of Viral Vectors,” Press Release, July 27, 2021
10. NIIMBL, “NIIMBL Announces 32 Projects Funded Under the American Rescue Plan,” Press Release, Dec. 20, 2021.
11. NIIMBL, “ARM and NIIMBL Release Project A-Gene,” Press Release, June 24, 2021.
12. ARM and NIIMBL, “Project A-Gene,” alliancerm.org, June 2021.
Jennifer Markarian is manufacturing reporter for BioPharm International.
Volume 35, Number 6
When referring to this article, please cite it as J. Markarian, “Coming Together to Enable Cell and Gene Therapy Manufacturing” BioPharm International 35 (6) 44-47 (2022).