Gene therapy is slowly stepping out of its niche, as new scientific insights and lessons learned from early-stage failures have led to several approvals. Now, manufacturing of the viruses used in gene therapy is about to become the next bottleneck. Can contract manufacturing organizations cope with the growing demand?

In 2017, Kymriah, a CAR T cell-based therapy to treat a form of acute lymphoblastic leukemia mostly found in children and young adults, and Luxturna, used for treatment of inherited vision loss by gene delivery to retinal cells, received FDA approval.

Thanks to the development of new virus backbone designs and mechanisms of action, gene therapy has become significantly safer and more effective. Especially when combined with other types of immuno-oncology drugs, such as checkpoint inhibitors, oncolytic virus therapy is regarded as a promising tool to attack cancer cells that evade the patient’s own immune response.

Overall, the range of diseases addressed with gene therapies is expanding, with hundreds of candidates in development, and many being evaluated in clinical trials.

 A bright future for gene therapy?

So can we expect a bright future for gene therapy? Yes—but only if manufacturing capacities can keep up with the growing demand. To make gene therapy available for more widespread use, cost of goods must go down—by expanding production capacity, introducing scalable production methods, and tailoring manufacturing systems to viral vectors.

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The range of diseases that can be addressed by gene therapy is expanding – manufacturing must keep up with the growing need

The high diversity and complexity of viruses used in gene therapy and the strict regulations required for good manufacturing practice (GMP) production limit the number of companies that are willing to take the challenge. And it’s not easy for newcomers to get on board, as the expertise required in viral vector GMP production takes years to build.

Fresh capital

Now, gene therapy has caught the attention of investors, and fresh capital has boosted the expansion of manufacturing infrastructure. One recent example is Biovian, a Finnish company that spearheads biologics contract manufacturing services since 2003.

Eero Mustalahti - Sales Manager

Eero Mustalahti, Sales Manager, Biovian

“With the recent investment, we are able to significantly expand our capacity and keep up with our customers’ growing need for GMP-compliant virus production,” Eero Mustalahti, Sales Manager at Biovian, tells us.

But money is not enough. Virus manufacturing for gene therapy is probably the most complex and resource-intensive process in biologics manufacturing. Or, as Mustalahti puts it: “It’s not just one, slightly variable product that can be produced on a standardized platform, like, for example, therapeutic antibodies. Viruses used in gene therapy are much more diverse, and require individually tailored manufacturing processes.”

Growing pains: Scalability

Typically when moving from preclinical to clinical phase, and ultimately, to commercial stage, scalability becomes an issue. For example, scaling up often requires switching virus expression hosts from adherent to suspension cell lines.

Biovian-Manufacturing-Gene-Therapy-Bottleneck-Manufacturing-Vials

Scaling up viral vector manufacturing is a finicky, complex, and resource-intensive process as it requires individually tailored processes

“This September, we will open our new 530 m2 extension dedicated to GMP process development. It will provide the space we need for an even higher technical variety of bioreactors and cell factories to flexibly address the growing demand for large scale production,” Antti Nieminen, director of business development and projects at Biovian, points out.

Purification methods must be equally scalable, which is why Biovian are shifting away from centrifugation procedures, and toward chromatographic methods. And with each scale-up step, strict quality control assays are mandatory to ensure that product quality remains unchanged.

Antti Niemien, CEO Biovian

Antti Nieminen, Director, Business Development and Projects

“To avoid delays and additional cost associated with late changes in production technologies, it is essential to have a good understanding of the required scale right from the start and design the process accordingly,” Nieminen says.

More challenges: Formulation, fill & finish

Next, down-stream processing and formulation conditions must be matched carefully to the features of each virus. The manufacturing process of adenoviruses, for example, is very sensitive to stress, temperature, and environmental factors that can lead to aggregation, affecting product yield and quality.

Biovian-Manufacturing-Gene-Therapy-Bottleneck

In-house expertise is one of Biovian’s pillars, allowing them to tackle the most challenging GMP requirements of virus production

Nieminen explains: “Aseptic filling of live viral vectors, container integrity, and design of packaging compatible with storage at –70 degrees C, are critical to meet GMP requirements, and often challenging steps.”

Safety first: Quality Control

Not surprisingly, Quality Assurance and Quality Control (QA/QC) are at the heart of GMP production. Biovian opened their new, EMA-GMP compliance-certified, 700 m2 QA/QC site in March 2018 to extend the capacity for analytical tests on product identity, purity, infectivity, endotoxin levels, and bioburden, as well as physical, protein-based, and cell-based assays.

“Being able to analyze all our samples in-house makes a huge difference,” Nieminen points out. “Not only does it speed up process development because we don’t waste time on tedious cross-audits or responsibility issues between different parties, but we also minimize the risks related to sample transfer logistics.”

A one-stop shop for virus production

The majority of Biovian’s customers are small to mid-size biotech companies that rely on a timely progress toward clinical trials. To them, a service offering that covers the entire development process can make all the difference, as it speeds up the entire process and minimizes the risk for delays and additional cost.

Biovian’s full oversight and control over their gene manufacturing processes makes all the difference for customers who value efficiency and transparency

“A key feature of our flexible service offering is that we take full oversight of each project to ensure a seamless integration from early development to the clinic and beyond. Our customers greatly appreciate this unique, one-stop shop concept: from gene to finished vial”, Mustalahti adds.

Keeping the personal touch

So what changes lie ahead for Biovian with the new investment? “Certainly, our goal is to become the leading European player in contract manufacturing of biologics. At the same time, we want to keep our company culture alive. We believe that personal contact, friendliness, and responsibility are essential in customer relationships. This is something we will maintain,” Nieminen concludes.

Learn more about Biovian’s expertise and how their one-stop-shop approach addresses current bottlenecks in GMP-compliant manufacturing of viruses and other biologics for gene therapy.

Images via Shutterstock, Biovian

Writer: Ute Boronowsky, PhD

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