Leveraging True Expertise and Flexibility for Lipid Nanoparticle Clinical Manufacturing

Leveraging True Expertise and Flexibility for Lipid Nanoparticle Clinical Manufacturing

December 14, 2021

Evonik’s Kristina Parrant, Senior Manager of Project Management, and Cole Byvelds, P. Eng., Senior Manager of Production, met with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D., to discuss the unique capabilities at Evonik’s Vancouver, Canada site for clinical-scale manufacture of lipid nanoparticles (LNPs).

David Alvaro (DA): Can you give me an overview of the capabilities for clinical manufacturing at the Vancouver site?

Cole Byvelds (CB): At Evonik’s Vancouver Laboratories, we primarily focus on preclinical development and phase I and II clinical manufacturing. We have a team that’s very well versed from both a technical and an operational perspective on working with LNP formulations, but also in working in that phase I and phase II space. Our capabilities are relatively broad and flexible, and we effectively translate that LNP know-how into clinical products, using both our knowledge and expertise in manufacturing within the dynamic and shifting clinical manufacturing space.

DA: What was the history of the Vancouver site before it became part of Evonik’s manufacturing network, and what drove Evonik’s interest in acquiring it?

Kristina Parrant (KP): We have been in the LNP space for over 30 years, and the site goes back to the early 1990s. It was initially owned by Northern Lipids, who did a lot of development and manufacture of novel lipid excipients. It was then renamed Transferra Nanosciences as the company expanded beyond lipids into formulation development and production of drug products. The Evonik acquisition occurred in 2016 and really shone a spotlight on the translational nature of the work. We benefit from the fact that Evonik also has large-scale manufacturing capabilities for lipids, active pharmaceutical ingredients, and other products and provides outsourcing services to pharma customers, while Evonik benefits from the complementary capabilities we bring to the portfolio.

CB: Evonik likes to be fully integrated throughout the value chain. By acquiring the Vancouver site, we now have preclinical to commercial drug product and lipid manufacturing capabilities all the way through fill/finish of final products. 

DA: What do you see as the most promising candidates for leveraging LNP delivery solutions, and where is the most activity currently, outside of mRNA therapies and vaccines?

KP: Outside of mRNA, LNPs are useful for the delivery of other types of nucleic acids, such as siRNA  and DNA. Beyond that, the next big applications will be in immuno-oncology and personalized medicine. Before the development of mRNA as a therapeutic for viral indications, many companies were working on mRNA-based immuno-oncology drugs and vaccines. While the COVID-19 efforts have really focused attention on what mRNA and LNPs can do for viral indications, work in those other areas is picking up now.  

DA: Have you seen greater investment in the mRNA space — and more broadly LNP technologies — and is there already growing demand for clinical manufacturing? 

KP: We’ve seen a huge increase in interest in what LNPs can do, with many companies evaluating how LNPs can be used to benefit their products and patients. And the truth of the matter is it can do a lot, including acting as an agent for existing APIs to optimize delivery and improve efficacy. The benefit of working with Evonik is that we have been in the LNP space for over 30 years. The COVID-19 vaccines are a proof of concept for a technology that at this site we’ve already known works for quite some time.

CB: There is definitely an energy in this space right now, and we are getting lots of inquiries about how fast and in what ways we can support potential customers. What is important is that, with our experience, the Vancouver team is able to provide a rapid response to inquiries about LNP technology. We’re well-versed from an equipment and process standpoint to ensure that customers get the product they need for clinical trials within the most aggressive timelines possible.

We are also gaining prominence on a global scale through Evonik, which further highlights the benefits of being a  smaller site that is nimble, as we can provide highly responsive products and services to our customers. There is a greater understanding about the Vancouver site and how we’re contributing in a massive growth area for lipid-based technologies. We are also seeing the process of integration into Evonik that was started when we were acquired accelerating, which further supports our customers getting what they need for late-stage and commercial manufacturing. 

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DA: Can you tell me a bit more about how Vancouver operates within the broader Evonik network and how the site benefits from that support?

CB: The clear link to the large-scale manufacturing facility in Birmingham, Alabama, allows us to transfer our products out when we get past that phase I or II clinical space while maintaining those customer relationships. As a result, we are able to support a broader range of customers. As a global company, Evonik also brings a strong sense of stability and continuous investment and allows us to leverage knowhow from across multiple sites on many levels, from process safety to capital project execution, and so on. And even though we have unique technology at Vancouver, there are still many common process-related resources that we’re able to draw on that provide new perspectives and value.

KP: And because we can help with both drug product and lipid delivery solutions and discuss the entire development pathway from early- to late-phase clinical and commercial manufacturing across the entire Evonik network, smaller customers in particular have a greater sense of security about their projects.

DA: How would you characterize the strengths of the unique LNP technological expertise that you have at the Vancouver site?

KP: The scientists and people in supporting roles here have been involved with lipid technologies for decades. Although the world is only now seeing what liposomes and lipid nanoparticles can do, the scientists here at Evonik Vancouver have been working to make that possible over the last 30 years. The technology is not new, and the expertise here is extremely broad.

CB: The LNP concept has been really cultivated and developed at the Vancouver site. We are fortunate to be a manufacturing site located in an area where extensive research efforts are ongoing in this field, allowing us to bring new technical competencies into the company as soon as they develop. Furthermore, to complement our scientists, we have extensive operational experience working with these formulations. The team with the technical background in formulation works closely with a strong manufacturing team that understands the nuances and unique aspects of working with these formulations. This makes it possible for us to not only rapidly implement practical manufacturing solutions but also to execute on them.  

DA: What customized equipment do you have for LNP manufacturing at the Vancouver site, and to what extent is Evonik designing, building or rethinking the fundamentals of production?

CB: While much of the equipment we use for clinical manufacturing is seemingly lab scale and may appear underwhelming in terms of size, it is no less complex than large-scale manufacturing systems. Core to manufacturing and production at Vancouver is the flexible, learning mentality of our scientists, operators, and other members of the production team, which gives us the ability to interface with a variety of this complex equipment.

Given this range of processes we work on, we have the experience and understanding needed to bring new equipment into operation from both the validation and training perspectives.

DA: What are the unique considerations and challenges for fill/finish of LNP-based products versus conventional biologics?

CB: As a result of our focus on the phase I and II space, we generally work with high-value, small-volume products. We build our fill/finish processes to minimize line losses and treat each drop of product as crucial. LNPs introduce additional challenges, but our team has the knowledge to set relevant fill/finish parameters to avoid negative impacts, given our extensive experience working with these formulations.

DA: What about unique analytical challenges? How is Evonik positioned to support analytics for manufacturing?

CB: We aim to be a holistic service provider, and analytics are a strong component of our capabilities.

KP: At Evonik Vancouver, we have analytical development and QC departments staffed with analysts who have competencies in both method development and QC of clinical products. They can perform the method development or transfer in and modify established methods as needed. Because the analysis of LNPs is not easy, the analytical development department here provides tremendous value. They have the know-how to generate novel methods and to fix assays that aren’t working.  

DA: For these high-value, low-volume LNP products, does the Vancouver site leverage automation, process analytical technologies, and other aspects of the Pharma 4.0 model?

CBs: The use of automation at Vancouver is targeted for those core processes that we pivot around. We also have a flexible automation strategy because we don’t run the same processes repeatedly. As a result, our automation considerations for production are really centered around human error reduction and ensuring that we’re getting consistency, while maintaining our flexibility to accommodate a variety of different products and processes. The goal is to help with execution and reduction of development times. 

DA: What kinds of customers do you serve at the Vancouver site? Is there a type of organization that makes the best organizational fit?

KP: We purposefully try to have a mixed portfolio of customers, both because it helps us innovate through broadening our experience and because we are positioned to bring value to many different types of customers. For instance, our formulation scientists can really help newer customers still trying to figure out how to work with LNPs, while our analytical group can support customers that have a formulation but are struggling with method development. We also help customers that have a formulation and manufacturing process but need help with fill/finish of the final product by leveraging our expertise in process optimization and aseptic processing.

CB: Flexibility and curiosity are part of the culture here, and part of what we offer is that comfort learning and working with new customers and a broad variety of formulations. As Kristina said, we deliberately provide solutions based on the API and compound to create the best possible drug product, and that’s part of our appeal and part of our value add.

DA: Has Evonik made any recent investments in LNP-related capacities or technologies? Is anything in the planning stages that you can discuss?

KP: Evonik’s LIPEX® liposome extruders were born at the Vancouver site, which is a good example of the company’s commitment to innovation. Recently, a new generation – the LIPEX® Flow extruders — was introduced, which enables higher throughput and improved reproducibility during liposomal drug production. This technology is really the culmination of Evonik Vancouver’s extensive history and expertise in the space. For LNP development, we are also working on cutting-edge micromixing technologies. In general, Evonik is committed to continued growth in directions that help the site and the company meet customer needs.

CB: Currently, Evonik is also making significant investments in human resources at the Vancouver site, including expanding our RD&I team and capabilities to ensure continued innovation in the LNP space. The two developments Kristina mentioned will really impact our customers in a positive way. Evonik is committed to continuous improvement with strong capital budgets and investment in people so the site will remain at the forefront from a technical perspective. We are well-positioned to build on our existing capabilities at not only Vancouver but other Evonik sites, such as Birmingham, in order to meet growing demand for LNP-based delivery solutions. 

DA: To close, what current or emerging trends are you following that could determine the future direction of need and demand for LNPs?

KP: One area of focus is developing the most efficacious mRNA (or other nucleic acid) therapies that can better support patients. Work is also being directed at developing novel lipids and lipid compositions with improved stability that are less dependent on temperature and the operational procedures needed to support such products. There is also interest in finding novel uses for lipid-based formulations. Personalized medicine will be a game-changer, and LNPs are delivery agents with real potential to support growth in this field and ultimately benefit patients. These are not new questions at the Vancouver site, and we have scientists working to develop those solutions.

CB: We knew that it was only a matter of time before this space exploded in the public’s eye. Now it is interesting to have these discussions with broader audiences beyond just our experts on site. With our dynamic and flexible work environment and extensive scientific experience in LNPs and liposomes, we are equipped to be a rapid-response provider from project intake through production. We can take on new projects, learn, work closely with clients, and really deliver on the timelines they need for even the most complex lipid-based products.

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