How do we solve the increased demand for accurate and and fast viral vector analytics?

The need for analytical technology that reveals the effect of production process on CQAs of viral particles in gene therapy and vaccines, and the most common analyses requested.

Vironova has been offering nanoparticles characterization and viral clearance testing services from its GMP compliant laboratory in Stockholm to biopharmaceutical clients for more than a decade. Recently, however, Vironova launched the MiniTEM, an advanced transmission electron microscopy (TEM) system, which combines hardware/software and automated image analysis so that developers can quickly review information about critical quality attributes - in house.

In this seven question (7Q) interview, Jonathan Royce, Instruments Business Unit Director at Vironova, source around the background to the increased demand for viral vector analytics and how automated TEM-based image analysis can provide objective, visual and quantitative data that reveal process impact on viral particle quality.

1. What analytics solutions does Vironova provide to support the development of viral particle based pharmaceuticals?

Jonathan Royce: Vironova provides analytical services and systems that scientists can use to evaluate the morphology, integrity, and purity of the viral vectors they are producing to insert the gene of interest into a patient. Our analyses are based on TEM, which allow for the generation of both visual and quantitative results. In product development, these analyses might be used to make decisions about things like manufacturing techniques, storage conditions, long-term product stability studies, and different types of formulations that might affect longterm product stability, for instance. In manufacturing, TEM can be used to generate quality control (QC) data during batch release. It might be used in an interim QC step to make stop/go decisions on a process. It can also provide insights necessary to investigate deviations that may occur in manufacturing.

2. We all know that the cell and gene therapy market has virtually exploded over the last couple of years, can you see any key trends in client requests and the kind of analyses developers ask for?

Jonathan Royce: Yes, we have seen several trends. In fact, Vironova’s history mirrors the development of drug-delivery systems and virus-based technology. We started by supporting several drug manufacturers that were developing liposome-based drug-delivery systems. That was followed by periods where viral-based vaccines for pandemic flu were a strong focus. Then in recent years, there has been a real explosion in AAV gene therapy. Most recently, in 2019, we have seen a big spike in requests for lentivirus analyses. Those trends are not unexpected when you look at the clinical pipeline; the earlyphase products that were based on AAV are starting to move into later stages, and now a wave of lentivirus-based products is coming.

It is quite analogous to what is happening in clinical development. Similarly, clients are requesting specific analyses that follow the clinical development of the various therapeutic types. For example, AAV manufacturers in the early phase of development are interested in looking at factors like particle integrity because their main focus is ensuring their vectors contain the gene of interest. At the same time, we are seeing more developers entering late-phase clinical manufacturing, and these clients are more interested in analyses related to purity. Once clients approach largescale and commercial manufacturing, the focus shifts to ensuring the downstream process is producing a pure product.

3. Vironova recently performed a market survey about the needs and challenges in analytics in the development and manufacturing of viralbased pharmaceuticals. Can you develop the reasoning, and if you got any actionable business intelligence for and from this study?

Jonathan Royce: We thought that it was important to gather some direct feedback from the developers of analytical techniques to understand the challenges and needs of analytical development laboratories in the biopharmaceutical space. The analytical field for viral vectors is still relatively undefined, so it is important that developers of analytical tools stay closely connected to development laboratories so that we can stay a step ahead of their needs.

"The analytical field for viral vectors is still relatively undefined"

For instance, early insights into the needs of lentivirus developers inspired us to create some artificial intelligencebased analysis methods that enable the quantification of polymorphic viral vectors, and which is nearly impossible to do using traditional analysis techniques. So, we use the insights gained from tools like surveys to ensure our technology is ready for when users need to implement it.

4. Did the survey findings match your experience of the trends you have mapped from client requests?

Jonathan Royce: Broadly speaking, yes. For example, as I mentioned previously, we are seeing more interest in lentivirus analyses, which the survey indicated is of growing interest in the market. We also see increased interest in purity analysis, which was confirmed by the survey to be a primary analysis of interest.

Another interesting observation from the survey was that, so far, not been much focus has been on ensuring that the analytical methods used for viral vectors are GMP compliant. A lot of this work is being done in the R&D laboratories, which is something that we at Vironova feel will be a very important requirement moving forward. Here too, we’re trying to stay a step ahead to ensure that our software, for example, will be GMP compliant in the way it handles data. When these analyses are ready to move from the R&D lab into the QC lab, our technology will be ready to make that move, as well.

5. In what way is the Vironova technology such a powerful solution for viral particle analysis in pharmaceutical development?

Jonathan Royce: When it comes to gene- and cell-therapy vectors, no other alternatives provide both visual and quantitative information. Several complementary technologies such as dynamic light scattering (DLS), ultracentrifugation, and surface plasmon resonance are on the market, however. These technologies, together with TEM, make up a package of orthogonal methods that is really powerful in fully characterizing a genetherapy product.

TEM has a unique position in this package in that one can extract multiple analyses from a single sample prep. Only a few microliters of sample are needed from which you can get quantitative results on purity and integrity, for instance. It provides direct visual confirmation of sample quality. People say a picture’s worth a thousand words, and that’s true even in the analytical lab. We’ve seen, for example, that the individuals who sign off on the release of a batch truly appreciate the extra security of a visual inspection.

People say a picture’s worth a thousand words, and that’s true even in the analytical lab. Seeing is believing!

6. What are the plans for developing the Vironova technology further? And what innovations can we expect from Vironova in the coming years?

Jonathan Royce: We’re going to continue to stay a step ahead of market needs and develop solutions that enable cell- and gene-therapy manufacturers. Expect to see continued developments in vector technology, for example, and we need to be close to those developments to ensure we have analytical solutions that match what’s coming into the clinical pipeline.

We also believe that automation will be key to improving the reliability of results, and therefore we’re working really hard to harness the power of informatics, electronics, and even fluid mechanics to minimize sources of error and streamline the entire analytical workflow.

We believe there’s enormous potential to use machine learning to streamline analytical development, and we’re working hard to bring the full force of AI into the analytical lab and enable users to train machines using their own proprietary data. So in one sense, we’re looking to democratize the technology of AI while, on the other hand, trying to ensure that every user can use their methods to differentiate themselves in the market.

And finally, we want to achieve these goals in a way that enables validation in GMP environments. This is critical - it’s absolutely going to be a requirement in the future for anyone trying to bring an analytical method into the QC lab that data is managed in a way that’s compliant with 21 CFR Part 11, and that the interaction with the software is controlled in a way so that users have one level of access while administrators have another level. We understand this very well at Vironova. We are not only developing analytical tools; we’re also providing analytical services for pharma and biotech companies, and we use our software in our own workflows.

Our lab in Stockholm has recently filed an application with the Swedish Medical Products Agency to become the world’s first GMP-certified freestanding QC laboratory for TEM analyses. We believe that the software we’re using in those analyses fulfills the requirements of Part 11 today and we’re committed to continuing to maintain compliance moving forward.

7. Expert or non-expert, if you want to learn more on how TEM rapidly can obtain meaningful nanoparticle characterization data for biopharma development, or just have a question to you - What is the way forward?

Jonathan Royce: That′s really simple and straight forward, just reach out to me here on LinkedIn or get in touch with Vironova′s TEM specialist at www.vironova.com and we/I will be happy to continue, develop or deep dive into the dialogue!

Finally if you found the topic intersting or know someone who would benefit of reading this interview, push the word forward.

"Sharing is caring"

Jonathan Royce is an experienced life science professional with broad experience in technical sales and marketing as well as customer-facing research & development, and has worked with process and product development, scale up and process modelling. He is the Director of the Instruments Business Unit at Vironova AB in Stockholm, Sweden. Jonathan holds degrees in Chemical Engineering from Northeastern University and the University of New Hampshire.