In this blog, three experts in the field of gene therapy from Andelyn Biosciences give their perspectives on challenges and opportunities in the industry: Dr. Samir Acharya, Associate Director of Process Development, Dr. Rajiv Vaidya, Head of Manufacturing Science & Technology (MS&T), and Cyrill Kellerhals, Head of Manufacturing. Providing their unique insights, they explore the challenges gene therapy developers and manufacturers are currently facing, those they can expect to see in the future, and, more critically, how they can be overcome.
Understanding the difficulties in process development
In the last 20 years, gene therapy research and development has rapidly evolved into the fast-paced and competitive industry we know now. The biopharma industry has seen a growing demand for viral vectors, like adeno-associated viruses (AAVs), and there is an expectation for these vectors to be of higher quality and produce higher titers and higher yields. To meet these demands, CDMOs must develop processes and platforms that are robust, scalable, and save time. In addition to higher titers, ensuring the quality of the final biological product is critical and should be the driver during process development. By incorporating quality-by-design (QbD) into process development, CDMOs can help accelerate timelines and ensure cost efficiency while providing robust and reliable manufacturing processes.
Flexibility to meet technological advancements
The gold standard purification step was previously considered to be ultracentrifugation, which removes other proteins and host cell impurities from the mix while enriching the full vector capsids – critical to the efficacy and immunogenic safety of the final product. However, as the field moves towards larger volume productions (using suspension or adherent platforms), ultracentrifugation of these large volumes becomes more space and time-consuming. Ultracentrifugation is also an open process which carries a potential increased risk of contamination. As a result, regulators are pushing for the use of alternatives, like column chromatography methods, to enhance patient safety. One of the challenges in the AAV field is the assessment of viral potency and tropism and the effect of differing platform processes and associated purification strategies on viral attributes. As better measures of potency and other viral attributes become available, flexibility is needed during process development to ensure that production and purification are effective, ensuring quality while also remaining compliant with changing regulations.
Other challenges come from the development of new AAV serotypes. Every serotype is different and will not behave the same way during the production and purification process, which makes a robust purification strategy key to final product quality. Process development will have to be flexible and adaptable to address the unique demands of new serotypes while ensuring both stability and high purity.
The importance of innovation and expert knowledge
Combining insights into the underlying mechanisms of disease onset with advances in biomedical engineering creates a platform for developing new gene delivery methods and associated cures. Process development teams must always be looking for new technologies while developing new assets focused on production, purification, and quality of the biological product. This includes ensuring that in-process analytics doesn’t rely upon one technique but rather uses orthogonal methods to evaluate product characteristics at individual steps of the process. Whether that be new platforms for faster production or the use of combinatorial chemistry to enhance titers, light-based or mass spectrometry-based technologies for assessing quality, or novel chromatography techniques for enrichment and purification of high-quality products, it is important to ensure that the technologies are cost-effective and timely for the client and patient.
Proactivity in science and technology solutions
Although a large number of rare diseases have genetic pathogenesis, the majority of rare diseases have no current treatments so there is a real drive to increase the production of gene-editing biologics to help this under-served patient population. In such a fast-moving space, staying on top of the latest developments is essential to meet these growing demands and ultimately help more patients.
Innovations in ex vivo and in vivo therapies
Viral vector and plasmid manufacturing require specialist knowledge along with the latest science and technologies integrated into production. There are currently over 2,000 gene therapies in the current pipeline1, highlighting the need for manufacturing support and the necessity for state-of-the-art facilities and equipment. This is the case for AAV gene therapy development and lentiviral vector production where the success of CAR-T therapies has driven demand for such vectors.
Technological advances to overcome future challenges
Meeting growing demand also requires an up-to-date understanding of the innovations in gene therapies attained from conferences, connections with academia (the source of major shifts in future trends), and communication with regulatory bodies. Being proactive in this way prevents future risks and ensures that changes can be made in the structure for new technologies and industry developments.
Biopharma companies looking to develop a gene therapy have many other pieces of the puzzle to keep in mind as they develop their programs – from regulations, meeting with regulators, clinical trial design, and analytical requirements. This process can be daunting, and support from external partners at the forefront of innovation can help alleviate the burden while supporting product delivery.
Manufacturing to meet demands and quality requirements
Competition in the biopharma space is growing and intensifying as new companies emerge regularly, making it tougher to succeed compared to five or ten years ago. As the market struggles and resources tighten, investors are demanding project progression through critical milestones with predictability and speed, as every extra day in development and manufacturing is an expense.
Manufacturing at speed while maintaining quality
One of the big issues gene therapy companies are facing is the need to maintain high product quality while delivering their product to market at an accelerated rate. Combating this challenge requires deep technical knowledge and collaboration, which is achieved through a robust manufacturing team that works closely with the analytical process development. Having facilities located close to each other also enhances the synergy between departments.
Meeting scaling demands
Staying on top of the latest trends and advances in cell line development is also important, particularly for cell culture. With this in mind, Andelyn Biosciences offers both adherent and suspension production platforms.
A current industry trend is a move towards the use of suspension cell cultures which enables the scaling-up of gene therapy. With that said, adherent cell cultures will remain a valuable and necessary platform for manufacturing gene therapies.
Expertise in both adherent and suspension cultures provides the flexibility needed to meet the needs of various gene therapy products and industry demands.
Key lessons
The principal advantages of external support are building partnerships and gaining expertise. Partnership with an experienced gene therapy CDMO like Andelyn provides clients with immediate access to their expertise – from process development to manufacturing and the integration of science and technology innovations. Andelyn is the supportive CDMO partner which can offer transparency and accessibility to its partners and clients at any stage in the drug development pathway to help meet milestones and streamline delivery.
To learn more about how Andelyn Biosciences can support your next gene therapy project, from preclinical concept to commercialization, please click here.
- https://asgct.org/global/documents/asgct-citeline-q3-2022-report.aspx