The Innovators Bringing Continuous Manufacturing to Lipid Nanoparticles

Abstract: The effective production of nanoparticles, particularly nucleic acid–lipid nanoparticle (LNP) products, hinges on a meticulously controlled production environment and close attention to all essential process parameters, suggesting an ideal fit for a continuous manufacturing paradigm. Technology startup DIANT Pharma has created an integrated production platform that encompasses the entire process — from nanoparticle generation through fill/finish — within a singular, streamlined system that enables the robust and scalable production of nucleic acid–LNPs and easy translation from the lab to commercial production, which has attracted interest from pharma companies of all sizes, as well as regulators. In this Q&A with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D., DIANT’s founder and Chief Executive Officer Antonio Costa, Ph.D., and Chief Commercial Officer William Pasek discuss the company’s unique history, the benefits of the technology, and what the future may bring to DIANT.

David Alvaro (DA): Tony, could you begin by sharing a bit of your own personal history, as well as that of the ideas that ultimately led to the formation of DIANT Pharma?

Antonio Costa (AC): My background is originally in biomedical engineering and pharmaceutical sciences, and I also have a solid grounding in electrical engineering, process engineering, software design, and now five years of operating start-up companies. I began working with nanoparticles — liposomes in particular — while participating in a pharmaceutical science program at the University of Connecticut (UConn). When looking into new grant opportunities, Dr. Diane Burgess and I learned that the FDA was offering grants in the area of advanced manufacturing. Leveraging my multidisciplinary background in biomedical engineering and pharmaceutical sciences, I was able to immediately suggest a project focused on continuous manufacturing for nanoparticle-based therapeutics.

A background in pharmaceutical sciences alone would not have taken us to where we are today. I wouldn’t have had the engineering mindset needed to design and build these new systems. In addition, that opportunity was great because my professor allowed her students to be more independent and flexible with their ideas. Rather than establish a rigid set of experiments for each student to perform, she provided a great deal of direction with the expectation that her students be self-sufficient and figure out the key concepts. That approach allowed me to develop a much better understanding of how to solve problems, which is essential to what we do every day at DIANT.

DA: Did you have a plan to create a company when you began developing the technology?

AC: Initially, I truly had no idea that we would eventually start a company. I was working on a project — a grant opportunity for which we were awarded funds. The first award was limited but allowed us to do pre-concept work. As we moved forward, we were able to win larger and larger awards — approximately $5.5 million in FDA funding went into development of the technology.

Once we filed the patent applications, we sought to license them out, which was what the university was hoping to achieve. We pitched the technology to companies as a licensing opportunity. Some discussions reached advanced stages, but ultimately nothing was realized.

Around 2019, the core patent was granted in the United States as a PCT (Patent Cooperation Treaty) patent, so we had coverage in different parts of the world. At that point, we decided we would try to commercialize it and started the company.

DA: What about you, Bill? Can you share a bit about your own journey that led you to your current role at DIANT?

Bill Pasek (BP): My background is in the commercial space in the industry. I started as a pharmaceutical sales rep. I was fortunate to work for GlaxoSmithKline for 15 years. It was during a time of tremendous success and growth. I had the opportunity to take on numerous roles and left the organization as Vice President of Sales — the experience gave me a great foundation in pharma, but somewhat of a unique one based in commercial brands. Next, I worked for 11 years at a midsize pharma company called Sunovion. We launched the brand Lunesta, which competed with Ambien, and my role was again on the commercial side, building a big sales force and a marketing team.

In 2015, I joined the contract development and manufacturing organization (CDMO) Avara, which afforded me a very different experience. Although I already had some manufacturing experience, it was probably the best thing I could have done because it opened up a whole other side of pharma. Avara had a range of capabilities across a number of facilities, and I learned a great deal about the complexities of pharma manufacturing. In 2020, I connected with Tony through a mutual acquaintance, and he described this new manufacturing technology in an incredibly hot space — continuous, nanoparticles, liposomes, lipid nanoparticles (LNPs). I was intrigued because I knew that the FDA was pushing for continuous manufacturing in pharma.

It has been a great experience. Avara had been somewhat of a startup. Back in 2020, DIANT Pharma was about as much of a startup as you can get — two guys in a garage — we have since that time morphed into an early-stage company with expanded capabilities.  We moved into a very nice facility with a growing and evolving staff, customers we are engaged with, and sales with various customers. In addition, the technology has evolved as well. We initially had one system purely for GMP commercial scale. Today, in response to customer feedback, we have two additional lines, including lab and pilot units, as well as a range of service offerings.

DA: What was it like trying to establish a new company during the COVID-19 pandemic? 

BP: Things proceeded at a slower pace than we had hoped. Lockdowns were an issue. Even though this technology is perfectly suited to a pandemic situation, as a new company, we weren’t developed enough as an organization to take advantage. We were still fundraising, determining the organizational structure, and so on.

AC: It is also important to acknowledge that the pandemic led to the first approvals of new mRNA vaccines and widespread knowledge about LNPs, which without COVID-19 could have taken 10 or 20 years. Today, mRNA–LNPs are at the forefront of medicine and have a bright future, and the space is also expanding to other nucleic acids and different types of nanoparticles based on different lipids, polymers, and more, for their delivery.

In essence, the pandemic really opened the door for DIANT Pharma because we had previously been focused mostly on liposomes and other types of polymers, which as it turns out have been slow to get market acceptance. Just a dozen or so liposome drug products have been approved, and that number hasn’t really changed since the 1990s. Without the interest in mRNA, there may not have been much of a driving force for advancing this type of technology. Now, there is growing interest from R&D all the way through commercial manufacturing.

DA: Can you give a high-level summary of the challenges in nanoparticle manufacturing that DIANT’s technology helps address?

AC: Our goal is to truly advance pharmaceutical manufacturing. Our focus has always been on continuous manufacturing and the development of a truly continuous, end-to-end process in which the API (nucleic acid or otherwise) is loaded into a nanoparticle in the upstream process, which is coupled with downstream operations. Such an approach allows for better control of the process stream through integration and increased automation, with fewer human interventions and less potential for error. Built-in controls, including sensors and feedback loops to inform the process in real time, lead to more consistent and higher-quality products. Ultimately, costs and timelines are reduced. In addition, scale-up is seamless because it simply requires running the process longer and/or running more equivalent systems in parallel, which allows for straightforward responses to changing market demand, as well as supporting scaling needs from personalized medicines to blockbuster drugs.

BP: Additionally, the reductions in costs that our technology enables free up resources that can be directed to other parts of an organization. We have been working hard to get the word out about DIANT Pharma and our technology, because drug manufacturers generally seek to work with people they know and trust within the industry. It takes time to cultivate those relationships and that sort of reputation. I think we’ve done a really nice job with the customer base we have been able to establish — they understand the technology and its benefits and are confident that it and the company are strong and will be supporting the industry many years into the future.

We have customers that are small pharma innovators and ones that are international players. Several CDMOs are also actively working with DIANT. Additionally, the fact that the FDA has acquired one of our systems has changed the narrative. We are not overly promoting that fact, but we emphasize that the agency is very interested in DIANT’s technology and what it might mean for the pharmaceutical manufacturing world. We hope to soon also be in a position to explicitly share some of the pharma and CDMO customers we are working with, which we think will also be a tremendous boost to DIANT’s reputation and recognition.

DA: Are the companies that you have engaged with all focused on LNPs, or is there also interest in other types of nanoparticles?

AC: Across the board, there is interest in many different types of nanoparticles, but the major emphasis in the pharma industry at the moment is definitely on LNPs. Even so, we have had great conversations about different types of nanoparticles for the encapsulation of small molecules, proteins, and all types of nucleic acids. There are many opportunities beyond LNPs.

For now, nucleic acids represent the largest share, and we expect that to continue moving forward, especially given that the FDA recently approved two CRISPR-based therapeutics comprising guide RNA and mRNA components formulated together as LNPs. That type of approval will further open the door for new nucleic acid–based modalities coming onboard in the near term.

DA: You currently offer a couple of different systems. What are the key differences?

AC: The systems are based on the same technology with respect to mixing, how the particles are formed, and the downstream operations. The differences are in the levels and flow rates. The LARU is our lower-cost system typically targeted for R&D applications, while the LIFT is geared more toward high volumetric throughput–dedicated continuous manufacturing in a GMP setting.

That doesn’t mean the LARU system can’t produce continuously, because it can. It is a much higher-value system and is offered for different purposes. It provides the high-quality results needed for R&D applications, but on a different level compared with what is required for commercial manufacturing. Results on the lab unit can be used to predict results with the commercial unit, which makes it easy to shift from lab to commercial production.

DA: What can you tell me about the options for scaling up versus scaling out with the DIANT systems?

AC: I think we have opportunities for both. We can definitely scale out if that is a requirement. In some cases, from a risk point of view, that may be more advisable and desirable. But scaling up for our particular system appears to be an easier approach. We start at the late discovery phase to early product development stage and scale from there, and we are more focused on scaling up at this time. But we do have the ability to scale out as well.

DA: DIANT Pharma has certainly evolved quite a bit in a short time. What can you share about your vision for the company going forward?

AC: We’re looking to become sustainable, and we have a good chance of doing that by 2025. There are plenty of opportunities and sales that we can land, which will put us in good shape. We would like to expand on our technology and broaden our product portfolio, which takes time, commitment, and proper funding.

With regard to the technology, our system is in a very good place at the moment. The systems that we offer provide very uniform particles, the best in the industry, and the systems are designed for CIP that can be cleaned in a very short period of time. But there are also opportunities with respect to developing a fully single-use option for our clients. Under certain conditions, that may be a better fit. Depending on the type of nanoparticle that is being produced, for instance, end-stage sterilization might not be possible, so having a single-use option could definitely be beneficial.

DA: Is there anything else in the pipeline that you can discuss?

AC: We have our 2TFF system, which is our continuous single-pass tangential flow filtration unit that can be used in many different applications. It is not only for nanoparticle concentration and separation but can also be used for small molecules, proteins, and potentially cells. As a standalone unit, it could really open new opportunities beyond the nanoparticle space.

There are several other areas outside of pharma that we could definitely focus on. Right now, our primary focus is the pharmaceutical industry, but there are plenty of other sectors that could take advantage of nanoparticles. We may start making those types of particles at some point, but that will be down the road, after we become sustainable.

BP: I would add that the last six to eight months we have seen a significant amount of interest in the 2TFF system as its own product. What is important to emphasize is that DIANT is sufficiently flexible and malleable to respond to and support any direction in which the market is moving. I think we’ll see more of that in the future.

DA: Is it challenging to manage all those opportunities — staying focused enough on one aspect without losing other threads?

AC: The focus now is on sales and marketing while also improving and optimizing the technology. Efforts today are focused on innovating the system design and developing solutions that address client requests.

BP: All organizations must evolve. That is true about technology as well. That is the beauty and strength of what DIANT can do — responding to customer requests with innovative solutions and identifying ways in which the technology developed three to five years ago can be improved. He is very good at maintaining that balance between running the company and keeping our innovative spirit alive.

DA: What do you want readers to know about the personality of DIANT Pharma?

BP: It is really a fun and exciting team. It is satisfying to see the responses people have when first introduced to DIANT’s technology. There is a tangible shift in their perceptions about what might be possible. The day-to-day work can be challenging, but everyone involved is committed and excited about the potential impact this technology can have on drug manufacturing and, ultimately, patients, which is the whole point.

DA: What is DIANT Pharma hoping 2024 will bring to the company?

BP: The first goal is an obvious one: achieve our revenue target. Next, I would say to hire four to five really talented folks that have that same entrepreneurial and optimistic spirit on the science/ engineering side and one or two on the commercial side. If we achieve those two goals, then we will be able to double the number of conferences we can attend, which in turn will greatly increase our exposure. A larger team will help with building our reputation and recognition level. Hiring the right people, hitting our revenue number, and increasing our exposure — if we do those three things, it will be a very good year for DIANT.