Navigating cell and gene therapy manufacturing with a long-term partnership

Analytical Development Consult

Cell and gene therapies have proven to be promising treatments for cancers and genetic diseases, but developers face key challenges before these treatments reach patients’ bedsides. A long-term partnership with a contract development and manufacturing organization (CDMO) can ease the path life science companies travel from manufacturing these life-changing treatments and bringing them to the patient.

Gene therapies can work in several ways, but often involve introducing a healthy version of a specific gene into patient cells, correcting the disease-causing gene. Cell therapies, on the other hand, transplant human cells to repair or replace damaged cells and tissue. Cell therapies can use a range of different cells, including stem and immune cells. The technology can be used for a variety of purposes, from treating cancers, autoimmune, and infectious diseases, to neurological disorders and spinal cord injuries.

Both technologies represent milestones in biomedical innovation, however, both cell and gene therapies are accompanied by challenges. Manufacturing costs can run high. Creating supply chains, arranging shipments, and scheduling manufacturing can all pose a logistical challenge. Moreover, global supply chains can complicate manufacturing further, as effective coordination and scheduling between suppliers and manufacturers on opposite sides of the globe can prove difficult.

For life science companies in the cell and gene therapy space, entering into a long-term partnership with a CDMO can go a long way toward addressing the challenges of manufacturing these treatments. By executing the different processes involved in developing and manufacturing cell and gene therapies through a single organization, such partnerships can increase speed, reliability and reproducibility. Additionally, long-term CDMO partnerships can reduce costs. 

Maturing technologies

David Chang, CEO of WuXi Advanced Therapies
David Chang, CEO of WuXi Advanced Therapies

“Cell and gene therapies are still maturing, emerging fields, which contributes to their high cost,” explains David Chang, CEO of WuXi Advanced Therapies, a global contract testing, development and manufacturing organization (CTDMO). “However, we can currently see cell and gene therapies evolving rapidly in preclinical animal models and early clinical studies.”

Many of the manufacturing processes involved in developing a cell or gene therapy are manual. Additionally, when processing material from multiple different patients, manufacturers need to ensure there is no cross-contamination between samples. These factors make efficient coordination of different manufacturing procedures more complex.

Furthermore, when it comes to autologous cell therapies like CAR-T, which use a patient’s own cells as opposed to a donor’s, demand is high: developers need to be able to provide therapies to large patient populations, as demand for CAR-T therapies surged after initial promising results were reported in leukemia and lymphoma.

“The operational scale needed to meet the high demand for CAR-T therapies requires a larger manufacturing footprint. It also requires a larger workforce because of the highly manual nature of manufacturing autologous CAR-T therapies,” Chang elaborates. 

Gaining approval

Once a cell or gene therapy has been developed, it must gain regulatory approval, and this is no easy task either. Cell and gene therapies are more complex than most other medicines because they use or modify whole living cells. By comparison, although biologics are made in living tissue, their active component is a single molecule.

“The complexity of a living organism or a gene is, by its nature, hard to characterize, control and measure,” says Chang. “Nonetheless, some regulators want to ensure that measurements are used that evaluate a cell or gene on a functional level – to find out whether it is potent and safe.”

“Part of the complexity of gene therapy is getting the gene to the right place and remaining there for the right amount of time – that’s just the efficacy part,” explains Chang. “But we don’t want that gene to go somewhere else unintended. Cell therapy faces similar issues in the testing and approval process.”

Another factor cell and gene therapy manufacturers must consider is whether their product requires specific growth serums to develop. There can also be cross-dependency between different types of cell lines in making a cell therapy. For example, some tumor infiltrating lymphocytes may depend on beta cells to secrete growth factors. Manufacturers need to take potential differences between serums and growth factor-secreting cells into account when developing cell and gene therapies.

Innovation gone viral

Adeno-associated viruses (AAV) are commonly-used vectors in gene therapies to deliver a gene to a patient cell. In addition to rare diseases and localized conditions, AAV-based gene therapies are also being developed for systemic conditions and diseases with large patient populations. These developments necessitate a scalable AAV manufacturing process. However, while AAVs have proven to be reliable, high costs and lack of scalability can limit their output.

WuXi Advanced Therapies is advancing AAV manufacture through two key technologies: AAVEX™ transient and TESSA™.

“Our AAV transient process represents a really great system for producing AAVs that rely on plasmid transfection,” explains Chang. “TESSA™, on the other hand, represents a truly novel, disruptive technology for AAV manufacture.”

The transient method of AAV manufacture involves transient transfection of three AAV plasmids into HEK293 cells. These cells then act as mini factories, producing the AAV particles that can then be used as gene delivery tools. The system employed by WuXi Advanced Therapies is genetically engineered to improve the AAV yield and infectivity above other plasmid-based approaches.

Unlike transient systems, TESSA™ and its components are stably integrated into AAV producing cells. Therefore, TESSA™ does not rely on transient plasmid transfection and is able to produce more uniformly infected cells. It is also more productive: when scaled up to 200 liters, TESSA™ can produce 30 to 40 times more AAVs than transient, plasmid-based approaches.

“By increasing the yield of AAVs, TESSA™ will help our customers to develop gene therapies in a more cost-effective way and to deliver them to more patients who need them,” Chang elaborates.

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Partnerships for the long-run

Entering into a partnership with a clinical development and manufacturing organization (CDMO) can be a major asset to life science companies tackling the challenges of manufacturing cell and gene therapies. Furthermore, long-term CDMO partnerships can lead to more efficient, streamlined manufacturing procedures.

In addition to providing cutting-edge technology, WuXi Advanced Therapies builds long-term partnerships in order to offer services across the entire value chain of cell and gene therapy manufacturing. These services go beyond the offerings of a conventional CDMO.

“What is perhaps most distinguishing about WuXi Advanced Therapies is our unique in-house capability to offer development, manufacturing, characterization, analytics and testing services – the value chain – to the client through a single contract testing, development and manufacturing organization [CTDMO],” says Chang.

“We can really help the client from the very early pre-clinical stage all the way to commercialization. That’s our mantra, and we take pride in building long-term relationships with clients,” Chang adds. “We are able to take the client from the DNA to the BLA [Biologic License Application of the FDA].”

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Looking ahead

Long-term partnerships with a CTDMO can lead to improvements and innovations that could potentially go beyond a single project.

“By partnering with developers through their whole therapeutic journey, we are able to anticipate future challenges and help to navigate around them,” says Chang. “There are real benefits in terms of cost and time saving when working with a single partnership over a long time. It makes the whole value chain more robust.”

Cell and gene therapies have made great strides in the last decades, with an ever increasing number of global clinical trials. With the opportunity to partner with a CTDMO, we may witness further advances in the field that continue to save lives.

Can WuXi Advanced Therapies assist you with your cell and gene therapy needs? Learn more about long-term prospects here!

Images courtesy of WuXi Advanced Therapies.

This article was originally published in October 2022. 

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