In this podcast, I spoke with John Ketz and Denis Kole about viral vector production, including current manufacturing challenges, navigating the road to commercialization, and successful scale up strategies.

We began the interview by discussing the strides made in cell and gene therapy. Denis shared information about the several  approved therapies and the more than 2,000 ongoing clinical trials. Denis added that while the immense potential of these personalized therapies is becoming more and more clear, the challenges and bottlenecks surrounding their development and manufacturing are also becoming a reality. This is especially true when it comes to producing and delivering sufficient amounts of these complex therapies in a reasonable timeline. He explained that patient demands are increasing and the increase in IND applications for cell and gene therapies is resulting in increased demand as well as competition for resources. Access to qualified labor has become a significant bottleneck and likely will continue to remain so, at least for the foreseeable near future.

He went on to say that the lack of standardized approaches for gene therapy modalities is another challenge that can increase the risk of failure. It can result in increased process complexity due to the need to screen large numbers of variables and can result in extended development times, which in turn affect the time to market for these needed therapeutics.

In addition, the availability of manufacturing capacity is also becoming quite limited with the field currently reporting a significant backlog that can extend as much as 16 to 18 months. John added that he also sees capacity issues and it is something that Andelyn Biosciences® is trying to address.

He also said that they are working on increasing speed and consistency. There are a lot of challenges that need to be addressed when moving from small flask or bench top scale into larger production scales. These may be challenges that you are not aware of or don’t encounter at small scale. It is important to be mindful of this during scale up.

ADDRESSING CURRENT MANUFACTURING CHALLENGES

To continue the discussion, I asked them to share the best way to address these challenges moving forward. Denis began by sharing that the demand for clinical and commercial manufacturing for advanced therapies is expected to continue to increase as more drug development companies entering the space and new therapies continuing their development journey. As a result, the manufacturing backlog currently observed will likely continue to remain present, if not expand. So, while large pharma and a few larger biotech companies may have the resources to internally support their clinical development and manufacturing needs, most of the smaller and medium sized drug development companies will continue to face challenges associated with quick access to qualified labor and access to extensive process expertise and available manufacturing capacity.

He went on to say that this is where groups like Pall’s Acellerator^SM process development services and Andelyn Biosciences can play an important role with support through partnerships and collaborations. These types of collaborations really can provide the necessary resources and support for therapy developers to target shrinking the development timelines, reducing the risks associated with process development, and scaling to commercial scale. In addition, Pall and Danaher’s integrated single use bioprocess offerings, provide scalable solutions that can reduce some of the risks associated with the development and manufacturing of therapeutics. These solutions really aim to alleviate some of the bottlenecks and risks associated with the lack of a standardized approach.

John added that at Andelyn Biosciences, they focus on creating a robust small scale model to ensure the consistency of the product when they move into larger scale. By doing this they can try to account for any of the differences that they might have, and can identify and define all of the critical process parameters throughout the whole process. Then they test the limits of all of these parameters in their model creation. He shared that working with a group like Pall, they have more consistency and confidence in the platform, so when they scale up, they know that it can work the first time and they don’t spend multiple rounds on large scale experimentation. John continued by saying that to address capacity issues, Andelyn is currently building a new manufacturing facility that will be able to handle additional large scale manufacturing for gene therapies that are coming online.

CHOOSING A SCALE UP PLATFORM

I then asked them if they could talk a little bit about the key factors that developers should consider in deciding which is the right technology for scale up. Denis replied that where the industry stands today, it is important to realize that there’s currently no one size fits all approach when it comes to production platforms and production systems for gene therapies. There are a multitude of factors that cell and gene therapy developers must consider when deciding what is the right technology and platform for scale up and  it is imperative to evaluate the target patient population size, the overall product demand, and the timelines that are associated with the clinical trial milestone. This work needs to be done in parallel with assessing the risks associated with each development and production platform and evaluating the advantages and challenges associated with each solution.

He said that he also believes that it is very important to think about a therapy’s commercial scale needs as early as possible in the development process. Starting this exercise early on, offers an opportunity to think about scalable manufacturing solutions early in the development process, and will likely lead to better process understanding and simplified transfer of the process to a manufacturing scale that meets the program’s needs. John added that it is imperative to have confidence in all the small bench scale studies to be able to translate those results into large scale production. It is helpful to work with a company like Pall to aid in the backlog of experiments and increased manufacturing demands by limiting a lot of the time spent on large scale experiments on your product.

SCALING UP AN AAV MANUFACTURING PROCESS TO 500 LITERS

Next, we talked about their upcoming webinar on how they scaled up an AAV manufacturing process to 500 liters. I asked them to share some of the highlights. John told me that he will be presenting how Andelyn used design of experiment studies for creation of a model that is robust enough at small flask and bench scale level to translate all of those optimized parameters into a 50 liter pool bioreactor. He will go into detail on their statistical approach and some of the results. He will also touch on some of the issues that they saw after moving from a small flask and benchtop into a 50 liter bioreactor. He will also discuss how they tech transferred that platform to Pall to help scale into a 500 liter bioreactor. Denis spoke next saying that optimizing and successfully scaling a viral vector process to manufacturing scale is not a trivial process. It requires extensive process knowledge and expertise, and one of the major hurdles is scaling the process while maintaining good process control, demonstrating equivalent productivity and maintaining product quality attributes. During the webinar, Denis will discuss how Pall’s Accellerator process development services team can support gene therapy development companies and then he’ll dive deeper into the specific approach that they took during the collaboration with Andelyn Biosciences. He will share some data that demonstrates the successful process scalability from the 50 liter scale to the 500 liter scale using the Pall Allegro™ bioreactor platform. The results demonstrated comparable viral vector production as well as comparable recovery between the two different scales, again using some downstream technologies like Pall’s Stax™ filtration platform.

I closed the interview by asking them if there was anything else that they would like to add for listeners. Denis said that we are living in really exciting times, the gene therapy journey through process development as well as industrialization is really a complex one, but the benefits of successful development and robust commercial processes are huge. We are all witness to the extraordinary impact that development and manufacturing of these therapies has on patients. John then said this is a very mission focused project for Andelyn, and their goal is always patient focused and patient oriented – that’s their #1 mission. All of Andelyn’s work has the end goal of improving people’s lives and it’s exciting to be a part of projects that are helping to drive the field forward.

To view the webinar, please register at Successful Scale Up of a High Yielding Viral Vector Suspension Platform to 500 L