Viral vector commercialization – Part 2: Best practices in process validation lifecycle
May 17, 2023 (11 minute read)
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Product and partnership quality in viral vector manufacturing: Your gene therapy depends on it
August 8, 2023 by Staff writer (7 minute read)
Category | Viral vector services
The promise of gene therapy is well established. By introducing, modifying, or replacing genes in a person’s cells to correct or compensate for genetic abnormalities, gene therapies target the underlying cause of the disease at the cellular level, leading to an effective treatment or cure.
Realizing this promise, however, requires the activation of several scientific, technological, and regulatory enablers. Among the most critical of these is the development of safe and effective delivery systems to transport the nucleic acids that encode the desired therapeutic protein into target cells. Unprotected nucleic acids are not stable in a biological environment, nor can they enter the cytoplasm (RNA) or the nucleus (DNA) by themselves. They need a Trojan horse that can get through the barriers and deliver the effectors where they need to go.
Enter viral vectors. These modified versions of naturally occurring viruses, such as adenoviruses, adeno-associated viruses, or lentiviruses, are engineered to be safe and efficient vehicles for transporting therapeutic genetic material into a cell. However, because viral vectors are inherently complex to produce at scale, the journey from bench to commercialization is rarely straightforward.
Navigating it requires maintaining a laser focus on quality to ensure the vectors are well characterized and consistently manufactured to rigorous tolerances of purity, potency, and safety. This is inherently challenging, both because viral vectors differ significantly in productivity and potency, and because regulatory standards for manufacturing and quality control are still evolving.
For biotech companies developing gene therapies, this means that quality—both of the viral vector itself and the CDMO partnership that enables it—must be a priority consideration when outsourcing viral vector development because it directly affects the efficiency, safety, targeted delivery, scalability, and clinical strategy of the gene therapy.
Viral vector quality
The characteristics of a quality viral vector can vary depending on the specific application and requirements. However, some universal quality traits include:
- High transduction efficiency. The vector should be capable of infecting a large percentage of the target cells to ensure successful gene transfer.
- Targeting specificity. Ideally, a viral vector should have the ability to target specific cell types or tissues, minimizing off-target effects and improving the safety and efficacy of gene delivery.
- Safety. A high-quality viral vector is minimally toxic and should not cause any adverse effects in the recipient. It should also have a low risk of disrupting or activating genes in the host genome.
- Stability and scalability. To maintain its efficacy, a quality viral vector should be stable during storage and transportation. It should also be easy to produce in large quantities.
- Low immunogenicity. Ideally, the viral vector should not induce a strong immune response in the recipient, which can lead to the destruction of transduced cells and limit the long-term expression of the therapeutic gene.
- Controlled gene expression. To achieve the desired therapeutic effect, the vector should allow regulation of gene expression.
- Large packaging capacity. A quality viral vector should have a sufficiently large packaging capacity to accommodate the desired genetic material without compromising its efficiency or stability. This is especially important for gene therapies that require the delivery of large genes or multiple genes simultaneously..
Partnership quality
At a high level, the defining attributes of a quality CDMO partnership are the same features that have been identified by industry partners as priority considerations across all therapeutic modalities. These include supply robustness, a solid regulatory track record, CAPA effectiveness, open communication, and business consistency, among others. With respect to the unique and specific needs of viral vector manufacturing, the following considerations are integral to a quality partnership.
- Expertise and experience. Viral vector manufacturing is a complex process that requires specialized knowledge and experience. Manufacturing partners that bring valuable expertise to the table, as evidenced by a proven track record in viral vector manufacturing, understand the intricacies of vector production, purification, quality control, and regulatory requirements.
- Facility and Infrastructure. Specific facility and infrastructure considerations may vary depending on the type of viral vector, production platform, and intended use, but basic requirements for a successful manufacturing partnership include a robust containment strategy for working with potentially hazardous biological agents; a facility layout that enables a smooth workflow and minimizes cross-contamination risks; state of the art cleanrooms and HVAC systems to maintain appropriate air quality and control contamination; enhanced containment strategies; reliable utility systems; and onsite quality control laboratories.
- End-to-end capabilities. Integrating all the stages of viral vector manufacturing (vector design and development, process development and scale up, cell line development, upstream processing, downstream processing, and formulation and fill-finish) into a cohesive manufacturing process under one roof minimizes the potential risks and surprises during development, simplifies the supply chain, improves predictability, and streamlines the path to clinic.
- Quality assurance and compliance. CDMOs with a strong focus on quality assurance and compliance implement robust quality systems, adhere to current Good Manufacturing Practices (cGMP), and have rigorous quality control processes in place. This scaffolding is especially critical in viral vector manufacturing because there is significant variation in technologies used for production and purification of viral vectors from one company to the next and regulations are not yet standardized across the industry. In the absence of viral vector-specific standards, manufacturers are left to determine how to apply regulations that were developed for traditional biologics while also ensuring their processes are safe and robust enough to remain in compliance as new standards are developed. Prospective manufacturing partners should be able to provide the specialized regulatory support as needed to stay ahead of the curve and leverage new developments.
- Scalability and capacity. The demand for viral vectors used in gene therapies and vaccines is increasing rapidly, but the complexity and cost of the manufacturing process, especially at the large scales to meet clinical and commercial needs, is a significant impediment to patient access. Partnering with a CDMO that offers scalable manufacturing capacity is a key consideration for overcoming this obstacle. Just as important, however, is working with a team that has the insight and the foresight to develop a process with scale-up capabilities early on. This includes choosing well characterized upstream and downstream products and technologies that are amenable to scale up, selecting raw material suppliers that meet the supply chain needs of for scaled-up processes, and ensuring regulatory compliance and quality are top of mind across all stages of development.
- Supply chain and risk mitigation. Viral vector manufacturing requires a robust and secure supply chain for critical raw materials, such as cell culture media, plasmids, and viral packaging components. Quality CDMOs have established relationships with trusted suppliers and can ensure the availability of high-quality materials. They also have risk-mitigation strategies in place to address potential disruptions in the supply chain, such as secondary sourcing options, inventory management, and contingency plans.
- Flexibility. Flexibility is vital for adapting manufacturing processes to meet changing regulatory requirements. It is also crucial for being able to scale up or down production processes based on the unique needs of a given program. Because viral vector manufacturing processes require continuous optimization to enhance yields, productivity, and product quality, flexibility enables manufactures to iterate and refine processes based on new information as it becomes available.
- Collaboration. Effective collaboration is one of the best ways to de-risk and accelerate viral vector projects. The hallmarks of robust collaboration are clear and open bidirectional communication; transparent information sharing; alignment on goals, expectations, and project objectives; clarity of roles and responsibilities; and integrated project management.
As evidenced by the defining characteristics, quality in viral vector manufacturing is a holistic endeavor that encompasses product, process, and partnership attributes. Developing gene therapy products that are clinically beneficial, commercially viable, and meaningful to patients requires harnessing all of them.
Learn more about partnership quality in viral vector development and manufacturing services.