Issue:September 2023
CELL & GENE THERAPY - Cell & Gene Therapy’s Everest – The Challenges & Opportunities That Will Shape Success
INTRODUCTION
Cell and gene therapies (C>s) are a rapidly evolving aspect of the biopharma industry, playing a significant role in shaping the future of healthcare and the treatment of genetic diseases. Despite the progress made in recent years, there are still many challenges and trends that must be addressed for C> to become a viable and widely used treatment option.
The following shares insights on the current challenges and trends in the field of C>, exploring the current and future challenges facing C>s developers and manufacturers and how to overcome them.
VIRAL VECTORS AS CELL AND GENE THERAPY TOOLS
Research and development has rapidly evolved into the fast-paced and competitive C> industry. Advances in gene-altering capabilities have played a big role in this evolution. Viral vectors are used regularly in C>s as they are excellent at delivering payloads into cells for genetic modification.
The viral vector and plasmid DNA market is expected to rise from $0.69 billion in 2021 to $1.38 billion in 2026, at a compound annual growth rate (CAGR) of 14.8%.1 Growth of the viral vector and plasmid DNA market is extremely important to the ongoing success of C>s, with many of these therapies using viral vectors as part of their mode of action.
The continued success of C>s relies upon continued advances to improve the safety and efficacy of these treatments. Further transformative change in C>s is likely to come from trends in process development, technology requirements, and quality requirements. These are three areas in which challenges are rife, and overcoming these challenges offers opportunities to create commercially viable and effective therapeutics.
UNDERSTANDING THE CHALLENGES IN PROCESS DEVELOPMENT
Process development is critical to the optimization and scaling of C> manufacturing processes as it enables the production of consistent and high-quality therapeutics. Although process development is vital, there are many challenges associated with it, and a future trend in the C> space will be to address them.
The biopharma industry is experiencing a growing demand for viral vectors, such as adeno-associated viruses (AAVs), and there is an expectation that these vectors meet high standards of quality, yield, and potency.
Quality should be the primary focus during the process development stage as it ensures the final product meets the necessary standards. Incorporating quality-by-design (QbD) into the process development can help accelerate timelines, cut costs, and establish dependable and robust manufacturing processes. QbD is a process concept in which product features are created and designed in response to customer requirements. Working with robust and reliable QbD processes takes advantage of the interwoven nature of timelines and budgets to streamline operations and reduce costs.
ADAPTING TO TECHNOLOGICAL ADVANCEMENTS
In viral vector manufacturing, ensuring effective process development requires the adoption of new and improved technologies. As these new technologies are developed, it becomes increasingly challenging to adapt and integrate them into existing processes.
Traditionally, ultracentrifugation (UF) was considered the gold standard method for removing empty vector capsids from viral vectors, which is vital for the final product’s efficacy and safety. Despite its effectiveness, UF is an open process and therefore has a higher risk of contamination than closed-process alternatives. As the industry shifts toward larger-scale production using suspension or adherent platforms, regulators are encouraging the use of closed-process methods, such as column chromatography, to improve patient safety.
Another challenge associated with technological progression in the AAV field is assessing the impact of different platform processes and purification strategies on viral attributes, such as potency and tropism. As more advanced measures of these attributes become available, it is essential to have flexibility during process development to ensure effective production and purification while staying compliant with changing regulations. Furthermore, newly developed AAV serotypes present unique challenges for production and purification, requiring adaptable and robust purification strategies to maintain final product quality and stability.
There are persistent challenges in testing for viral quality at both small and large scales, as well as controlling the quality of the development process. Common issues for quality control appear when scaling up or scaling down. Maintaining quality at either end of the scale is crucial to meeting regulatory requirements and necessitates sufficient technological capacity for consistent quality control.
INNOVATION & EXPERT KNOWLEDGE
Process development must aim to ensure cost-effective and timely C> production to meet rising demand and deliver critical therapies to patients. To achieve this, drug developers must apply expert knowledge to integrate innovative techniques and technologies into processes.
Process development teams should continuously search for new technologies while creating new assets for producing, purifying, and assessing the quality of C>s. This involves utilizing multiple techniques for evaluating product characteristics throughout the process, such as using new platforms for faster production, combinatorial chemistry to improve titers, light or mass spectrometry-based technologies for quality assessment, or novel chromatography methods for purifying high-quality products. Biopharma companies are also integrating data mining and analytics to improve their manufacturing processes. By connecting various data points, it’s possible to boost yield and efficiency, decrease costs, and enhance the consistency of outputs. This type of data utilization is becoming increasingly important in the industry and will be used more in the future, although potential difficulties in integration with the existing framework could occur. Combining insights into the underlying mechanisms of disease onset with advances in biomedical engineering creates a platform for developing new C> delivery methods and associated cures.
STAYING CURRENT WITH CELL & GENE THERAPY ADVANCEMENTS
Manufacturing viral vectors and plasmids require specialized expertise and the integration of the latest science and technologies. With 3,649 C>s in the pipeline, there is a need for manufacturing support and state-of-the-art facilities and equipment.2 In this rapidly advancing field, it is crucial to stay informed about the latest developments to meet the growing demand for C>s and benefit to patients.
A lack of effective treatments for certain diseases has driven many developments in C> technologies. In particular, many rare diseases are caused by single genetic abnormalities, but most have no existing treatments. This has pushed the need for enhanced technologies and to increase the production of gene-editing C>s to help this underserved patient population.
TECHNOLOGICAL ADVANCEMENTS
One of the major challenges facing C> developers is targeting therapeutic delivery to the right location in the body and ensuring the immune response is minimal. These are areas in which C>s are constantly advancing to the benefit of the C> industry and patients receiving therapeutics. The development of novel serotypes and delivery vehicles like lipid nanoparticles (LNPs) allow for tissue-specific and targeted delivery of C> and reduce the risk of an adverse immune response. Improving the efficiency and quality of viral vectors is a significant step to achieving the desired therapeutic effect without off-target toxicities.
CRISPR-based technologies are advancements in genetic modulation that are increasingly used for C>s. CRISPR-Cas9 is a powerful tool for precisely cutting and editing genes, and it has been used to treat a wide range of genetic diseases, including sickle cell anemia, Tay-Sachs disease, and certain cancers. CRISPR-based gene regulation methods also hold great promise for precise and long-term expression and have the potential to change the C> industry through precise, efficient, and cost-effective genetic manipulation. The low costs and improved delivery of CRISPR-inserted genetic material via viral vectors enable faster timelines for scaling up and commercializing gene therapies.
FUTURE CHALLENGES IN THE CELL & GENE THERAPY SPACE
C> developers and manufacturers must stay informed to incorporate innovative techniques and technologies and effectively meet increasing demand. Keeping pace with the latest C> advancements requires attending conferences, collaborating with academia, and communicating with regulatory bodies. Proactive measures like these help mitigate potential risks and allow for timely adjustments to the industry’s structure in response to new technologies and developments.
Staying abreast of advances and effective collaborations also goes beyond technology. Developing a C> involves multiple considerations for biopharma companies, such as regulatory compliance, establishing relationships with regulatory agencies, clinical trial design, and analytical requirements. These processes can be challenging, and partnering with external innovators can help ease the burden and facilitate successful product delivery.
MANUFACTURING TO MEET DEMANDS & QUALITY REQUIREMENTS
Aside from process development and integrating innovative technologies, progressing and reinforcing manufacturing quality is a key trend for developers within the C> space. This trend affects the whole biopharma industry as new companies enter the market and competition increases.
The pressure is on for C> companies to make the most of investment resources and bring high-quality therapeutics to market quickly to avoid costly delays in development and manufacturing. Avoiding delays requires expertise and collaboration from a manufacturing team that works closely with the analytical process development team. Additional factors like having facilities located in proximity to each other can also help streamline timelines through more effective collaboration and coordination between departments.
MEETING SCALING DEMANDS
Remaining informed about the latest developments in cell line development is crucial, particularly when it comes to cell culture. Achieving this requires expertise in both adherent and suspension production platforms. One trend in the industry is the increasing use of suspension cell cultures for scaling up C> production; however, adherence-based cell cultures will still play an important role in manufacturing these therapies. Being proficient in both types of cultures allows for the flexibility to accommodate the various requirements of different C>s products and industry demands.
Being well-informed about the needs of cell line scaling helps make informed decisions on cell line development. Instead of automatically opting for a suspension cell line for its scaling potential, an adherent cell line is more appropriate. Depending on the indication, virus requirements, or therapeutic target, an adherence-based cell culture may be more effective. External manufacturing expertise can aid in making these complex decisions, ultimately increasing the chances of success.
Creating stable cell lines will be a major technological advancement for the production of C>s moving forward. Instead of relying on transient transfection, the focus is shifting toward generating stable cell lines because of the following advantages:
- Consistency of vial vector quality: Once a stable cell line is developed, it provides a reliable cellular source of viral production with consistent quality and potency.
- Scalability of production: Stable cell lines can be expanded in capacity to produce large quantities of viral vectors, which can be crucial to the commercialization of C>s.
- Cost-effectiveness: Stable cell lines can be maintained in the laboratory for prolonged periods, reducing the need for repeated isolation and expansion of cells from primary sources.
- Time efficiency: Stable cell lines are easy to handle and maintain, which helps with scalability and meeting short timelines.
- Compliance: Stable cell lines can be characterized and validated to ensure and demonstrate their consistency, purity, and identity to regulators.
KEY LESSONS
The treatment potential of C>s is only just starting to be realized, and the increasing demand for treatments will help drive funding in the space. As the C> field evolves, it is becoming more critical than ever drug developers evolved convergently. This will require developers to embrace the transformative change within C> and the wider biopharma industry and be open to the key trends discussed within this article.
Addressing the challenges of implementing better process development, technological advancements, and quality requirements for C> need a collaborative and open approach. Successfully overcoming these challenges will present opportunities for companies to thrive in the competitive C> industry and produce treatments of great value to patients.
REFERENCES
- https://www.reportlinker.com/p06241861/Viral-Vectors-And-Plasmid-DNA-Global-Market-Report.html?utm_source=GNW.
- https://asgct.org/global/documents/asgct-citeline-q3-2022-report.aspx.
Dr. Samir Acharya is Associate Director of Process Development at Andelyn Biosciences, where he is responsible for Process and Platform Development, their optimization characterization, and technology transfer. Prior to Andelyn Biosciences, he spent over 25 years of research experience in mechanisms of genomic instability and pathways of cell survival and proliferation. His expertise is in the fields of biochemistry, molecular and cell biology, and cancer. He has extensive experience in assay and method development utilizing tools involving molecular and cell biology, molecular genetics, microbiology, microscopy, protein purification, biochemical/biophysical analyses, and enzyme kinetics. He earned his BSc in Chemistry from St. Stephen’s College, University of Delhi; his MSc in Biotechnology from Jawaharlal Nehru University, and his PhD in Biochemistry from Indian institute of Science, Bangalore, India.
Dr. Rajiv Vaidya is Head of Manufacturing Science and Technology at Andelyn Biosciences. He has over 25 years of experience in research and development in academia and industry. Prior to Andelyn, he was Sr. Director of Manufacturing at Grace Science LLC, a biotech company focused on NGLY1 gene therapy. His previous positions were at Arranta Bio, Brammer Bio, and Meridian Life Science. His functions in previous companies were related to manufacturing, process development, and technical operations for Gene Therapy products, native viruses, recombinant proteins, and antibodies. He earned his PhD in Microbiology from Maharaja Sayajirao University of Baroda, India.
Dr. Laura A. Kerepesi is the Associate Director of Preclinical Manufacturing at Andelyn Biosciences and has been part of the Andelyn team since early 2014. She has over 20+ years of R&D experience from opportunities at Battelle Memorial Institute, Thomas Jefferson University, The Ohio State University, and Nationwide Children’s Hospital. Her experience includes immunology, infectious disease, vaccine, and cancer research, viral vector process development, and preclinical upstream and downstream AAV manufacturing scale-up. She earned her PhD in Immunology/Parasitology from Thomas Jefferson University.
Cyrill Kellerhals joined Andelyn Biosciences in 2021 and oversees both viral vector and plasmid GMP manufacturing. He has over 20 years of Quality and Manufacturing leadership experience across Asia, Europe, and North America in the Pharmaceutical, Biopharmaceutical, and Medical Device industries. He earned his BSc in Chemical Engineering, and his MBA with a specialization in Business Analytics from Whitman School of Management at Syracuse University.
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