While the global gene therapy market grows steadily, companies continue to face bottlenecks in the production of gene therapy’s essential building blocks: viral vectors and plasmids. Here, we compare the manufacture of viral vectors with that of recombinant proteins and reveal how one company has developed a solution to address the continuing challenges in gene therapy production.
As the global gene therapy market expands, the need for viral vectors and plasmids increases. In 2019, the global gene therapy market was valued at $3.8B (€3.18B); the global viral vector and plasmid manufacturing market was worth $368M (€308M). By 2024, the global gene therapy market is estimated to reach $13B (€11B).
But, despite these promising forecasts, drug developers are confronted with manufacturing complexity. Compared with the production of recombinant proteins, for instance, the production of viral vectors is a lot more challenging. There are several reasons for this.
Viral vector vs. recombinant protein production
“Viral vectors are much more complex than recombinant proteins,” said Antti Nieminen, Director of Business Development and Projects at Biovian, Turku, Finland. “Recombinant proteins are relatively simple molecules made up of 20 different amino acids linked in chains and expressed by well-characterized cell lines and established expression vectors.”
Viral vector production, on the other hand, can utilize various different cell lines, each with unique growth and transfection characteristics. In the case of adenoviral- (AV), adeno-associated viral (AAV)-, and lentiviral (LV) vector manufacturing, a characterized master cell and respective viral seed stock, and/or transfection plasmids are needed as well. This adds to the complexity of the process.
A further challenge is that all supporting reagents need to follow good manufacturing practice (GMP) guidelines to meet regulatory authority requirements.
“While manufacturing of recombinant proteins is a fairly straight-forward process, starting with simple raw materials, manufacturing of viral vectors involves some advanced materials, such as plasmids, which also need to be manufactured according to guidelines,” Nieminen said. “In other words, viral vector manufacture involves several parallel tracks that should all fulfill good manufacturing practice, GMP.”
Moreover, “the processes for manufacturing biopharmaceutical recombinant proteins are well established and straightforward, so regulatory guidelines can be followed smoothly,” Knut Ringbom, CEO at Biovian explained.
“But the advanced therapy medicinal product guidelines for viral vectors are newer than those for recombinant proteins and there is less experience from their interpretation, so drug developers have less experience in the implementation of these guidelines.”
Filling knowledge gaps in process development and regulatory affairs
While academic groups and biopharmaceutical companies are scientifically highly experienced, they can lack the necessary process development, manufacturing, and regulatory knowledge for successful viral vector GMP production. Here a collaboration with an experienced contract development and manufacturing organization (CDMO) may mean the difference between success and failure.
“An expert CDMO partner can provide guidance on the ATMP procedure, as well as on producing or sourcing of specific GMP-grade components, reagents, and consumables,” Ringbom explained.
“When the collaboration between a CDMO and a client begins, a decision has to be made about the viral vector manufacturing process. What manufacturing platform to use, how to source plasmids, who will create the production cell line, and so on. All that adds up to a complex package where an expert CDMO may be of crucial assistance before you are ready to go into clinical manufacture.”
An experienced CDMO partner can support a biopharma client with all these decisions and lead them through the different stages of viral vector production, including process development, analytics, scale-up, GMP manufacturing, and regulatory guidelines, just to mention a few. “We can use the experience we have gathered over the years, so the client doesn’t need to start investigating everything from scratch,” Ringbom added.
The ‘one-stop-shop’ solution clears bottlenecks in gene therapy production
In fact, Biovian has well over a decade of experience in both recombinant protein and viral vector contract development and manufacturing. The CDMO takes a so-called one-stop-shop approach to facilitate gene therapy production inefficiencies. In other words, all of the steps in recombinant protein and viral vector production can be done under one roof.
Biovian’s one-stop-shop runs along two axes: the supply chain and the value chain, with each stage adhering to GMP guidelines and based in fully certified facilities. Along the supply chain, Biovian supports its clients in all areas of master cell banking, upstream and downstream processes, aseptic fill and finish, qualified person release, and full GMP certification.
Biovian’s services on the value chain involve everything from preclinical supply to clinical and later commercial supply. This way, Biovian can lead its clients through their molecule’s development to commercialization, while providing regulatory support throughout the project.
Supporting clients all the way from start to finish
“Let’s say a company approaches Biovian,” Nieminen said. “We can immediately start with manufacturing the master cell banks and plasmids, or the viral seed stocks. Then we set up all the analytics, run small-scale batches, go into the GMP facility, and run the first technical/engineering batch, which will usually be used for nonclinical studies. From there, we can go directly into GMP drug substance manufacture.”
“The beauty of working with a true one-stop-shop like Biovian is that we can directly continue from the drug substance manufacture to the aseptic filling of the final containers, such as vials, which will undergo full quality control, labeling, and clinical packaging. Then, one of our qualified persons will release the drug substance to be shipped out to the clinic.”
In short, this means that Biovian’s clients are not forced to shop around for one company to do their process development, another firm to run the analytics, another to perform the drug substance manufacturing, and a fourth to prepare the drug for clinical trials.
“A project scattered around companies is much riskier. Quality issues emerge when multiple players are involved. With us you get everything under one roof, which can mitigate risks and save a lot of time and money,” concluded Nieminen.
Catering to the evolving needs of gene therapy and recombinant protein manufacturers
To address gene therapy production capacity constraints for viral vectors and plasmids, Biovian has recently expanded its GMP viral vector manufacturing facility. This has doubled the company’s capacity to produce viral vectors for gene therapy development. Its 200L bioreactor can now serve clients when taking their gene therapies into late-phase clinical trials and even to market.
Moreover, Biovian is continuing its one-stop-shop expansion by adjusting its capacities to the needs of its biopharma clients. In 2021, the company is planning to open a fully automated aseptic filling line for plasmid DNA and recombinant proteins.
“It is essential not to neglect recombinant protein production, as it’s an incredibly important sector as well. At the same time, it is unique to have all components available needed for the production of viral vectors, including plasmids and vialed products. I believe this is the major reason why clients come to Biovian. We have done this before,” Ringbom concluded.
Header image via Shutterstock.com, all article images via Biovian