The use of lipid nanoparticles (LNPs) as non-viral delivery tools for messenger RNA (mRNA) helps alleviate the otherwise poor pharmacokinetics (PK) and in vivo instability of mRNA. However, LNP formulation development and manufacturing remains complex and challenging. LNPs directly impact the efficacy and safety of the drug and as such, improvements to the formulation during clinical trials require significant time and human studies. Large scale CGMP manufacturing is also difficult and requires improvements to standardization, scalability, and reproducibility as the industry expands use of mRNA technology to multiple therapeutic applications.

In the following interview, Jingtao Zhang, Ph.D., Scientific Director at Catalent Biologics, answered some frequently asked questions about the challenges with lipid nanoparticle development and manufacturing:

What are the challenges associated with development and delivery of mRNA therapeutics and vaccines?

Safe and effective delivery of mRNA has been one of the major hurdles to wider use of the technology, due to its inherent instability and inability of mRNA to reach the target site of action. mRNA acts inside the cytosol, so it needs to be transported across numerous extracellular and intracellular membranes after dosing. Of the different membranes, the most formidable is the cellular membrane including endosomes and lysosomes, which is non-passable for large nucleic acids. In addition, mRNA has a short half-life in the body, resulting in reduced activity before reaching its target. Hence, use of mRNA in therapeutic or vaccine applications results in very poor efficiency or is non-practical without a carrier system.

What solutions are available to overcome these challenges?

Pharmaceutical scientists have been leveraging synthetic carrier systems to improve the transport of mRNA across membranes and improve the overall stability of mRNA in the body. These carrier systems behave like packaging systems, encapsulating large mRNA molecules inside tiny particles. This type of packaging offers several advantages, including decreased degradation by enzymes, increased uptake and cytosol penetration, and improved tissue penetration. In the last two decades, numerous particle-based systems have been explored with the focus of non-viral applications being on polymer and lipid-based systems.

Why have lipid nanoparticles emerged as a common solution to these challenges?

Lipid nanoparticle technology has gradually progressed over the past several decades before it finally emerged as a solution for large scale vaccine use. There are several advances in different applications that propelled it to the current formulation:

First, liposome-based technology was developed for the delivery of small molecule drugs and came to be known as “nano” delivery. The overall understanding in stealthy liposomes (to deliver active molecules to the site of action), liposome stability, and composition plays an important role in determining current formulation components.

Second, the advancement in manufacturing technology for lipid nanoparticles stems from its early application in plasmid DNA encapsulation. This type of technology made it possible to manufacture the particles in a reproducible manner.

Finally, the application of lipid nanoparticles for siRNA really catalyzed their use for encapsulating mRNA, as the use of LNPs for siRNA has shown LNP to be safe and effective in humans. mRNA delivery also benefited from the intense optimization of lipids during the process of siRNA discovery.

What challenges are associated with LNP formulation development and manufacturing? What are some solutions to address these challenges?

Despite the commercial success of LNP technology in vaccines and therapeutics, their formulation development and manufacturing has remained both complex and challenging. In traditional drug formulation, excipients can be exchanged during clinical trials to help improve bioavailability and/or the stability of drugs. These can occur with or without a clinical bioequivalence study. Currently, lipids used in formulation are considered active components and are approved alongside the API. Interchange of the lipid components is not possible without extensive safety and efficacy studies in humans. Thus, formulation development is a critical path activity for any preclinical or clinical study.

Many formulation matrices can be utilized for LNPs. However, exploration or testing of these has been very limited due to limited clinical trials conducted to date. Until now, most companies have focused on a small set of compositions and chemistries already proven in commercial use. Hence, intellectual property competition in the space is intense and may limit a developer’s freedom to operate.

Overall performance of LNPs in different tissue or target organs are highly dependent on the LNP formulation and chemistry. This is both a challenge and opportunity for innovators, because as exploration increases, the use of LNP-based formulations can help with product differentiation and create strong intellectual property.

Large scale manufacturing of LNP in a CGMP setting has been a significant challenge, although multiple companies, including pharma, biotech, and CDMOs, are working quickly to fill that gap. In most cases, unique bioprocess unit operations and customized equipment are required. Current manufacturing equipment for LNP were not considered fit for purpose even though they have been used to manufacture products that are authorized for emergency use. Standardization, scalability, and reproducibility of LNP manufacturing will become more and more critical as we move toward niche applications that will have their own challenges associated with smaller, potentially infrequent, batches.

For more information, please see: https://biologics.catalent.com/specialty/mrna/

Don’t miss our other mRNA Ask the Expert Sessions:

mRNA: A New Option for Vaccines and Therapies
In our Ask the Expert session with Wai Lam Ling VP Scientific Advisory at Catalent, she answers questions about mRNA and its use in vaccine and other therapeutics. Our discussion included additional indications, challenges and opportunities to advance current practices.

mRNA Development and Manufacturing: CMC Challenges and Solutions
In our Ask the Expert with Jingtao Zhang, he discusses the increased demand for mRNA-based vaccines and treatments and the challenges associated with mRNA manufacturing. We talk about solutions including building additional GMP capability dedicated to mRNA processes, integrated development and manufacturing capabilities for plasmid DNA, mRNA, lipid nanoparticles, fill finish, and clinical supply services as well as analytical testing and characterization capabilities for this complex modality.

About the Expert

Jingtao Zhang, Ph.D., Scientific Director, Catalent Biologics

Dr. Jingtao Zhang is a Scientific Director, Catalent Biologics. He has more than 16 years of experience in the pharma and CDMO fields, building new business offerings, discovering and developing drug products of small molecule, peptide, oligonucleotide/siRNA, biologics, mRNA, LNPs, and nano-therapeutics. At Catalent, Dr. Zhang serves as a technical advisor for the group and is responsible for developing new technical capabilities and product solutions to solve clients’ pressing pharmaceutical problems.

Prior to Catalent, Dr. Zhang was a principal scientist in the Department of Pharmaceutical Sciences at Merck & Co., Inc. (Kenilworth, New Jersey). His product experience includes early discovery, candidate nomination, early product development, late-stage product development, and commercial investigations, with in-depth knowledge of drug development paradigms and regulatory requirements. His expertise is in formulation development, protein stability, new modalities (mRNA, siRNA, peptides), and complex drug delivery systems such as LNPs. He received his Ph.D. in Chemical Engineering from the University of Wisconsin-Madison. He has authored/co-authored more than 30 articles in peer-reviewed journals and delivered more than 30 presentations at national and international conferences to date.