Feasibility Studies and cGMP Design Supporting Continuous Lipid Nanoparticle Manufacturing
Author: Jim Ziogas, Sales Engineer, DIANT®
Abstract: The successful manufacturing of nanoparticles (e.g., lipid, liposomal, polymeric) for pharmaceutical applications requires skilled and meticulous formulation and an optimized process. The DIANT® continuous manufacturing technology and product development services provide a highly efficient and cost-effective solution for achieving more accurate nanoparticle size and more consistent encapsulation of payloads. With a focus on data integration, process efficiency and cost-effectiveness, DIANT® empowers drug developers to gain a competitive edge and expedite the delivery of lifesaving medicines, vaccines, and health products to those in need.
Need for Improved LNP Manufacturing Technology
Lipid nanoparticles (LNPs) have emerged as the preferred carrier for nucleic acids, highlighted by the success of mRNA vaccines against COVID-19 developed by Pfizer/BioNTech and Moderna. This success has sparked a surge in the development of drugs and vaccines utilizing various types of nucleic acids, igniting enthusiasm for their potential to offer not just therapeutic but curative solutions to previously untreatable disease states.
However, achieving successful LNP formation at scale poses significant challenges. It necessitates high-quality nucleic acids, an optimal lipid formulation to ensure stable particles, a consistent mixing process to generate uniform particles, efficient solvent concentration and removal, appropriate surface modification techniques, and effective purification solutions. Understanding the entire manufacturing process comprehensively, with access to real-time data from start to finish, is paramount, particularly at large production scales. Throughout the process, subtle changes occur in the nanoparticles, and monitoring these changes is crucial for ensuring particle stability.
While these aspects of nucleic acid–LNP manufacturing can generally be well-controlled at small scales, maintaining consistency becomes increasingly challenging as production is scaled up. Implementation of a continuous LNP manufacturing process encompassing formulation through to fill/finish presents an ideal solution for achieving robust and scalable production. Operating within a closed system, with minimal human intervention, reduces the risk of errors and contamination. Moreover, minimizing hold times between steps decreases the likelihood of destabilization and degradation, resulting in LNPs with uniform particle distribution and high encapsulation efficiency.
DIANT® was established with the aim of commercializing groundbreaking continuous nanoparticle manufacturing technology. Initially developed by researchers at the University of Connecticut with FDA/NIH awards of approximately $5.5 million to the university, further fueled by the FDA’s growing interest in advanced manufacturing solutions for continuous processing, the company took shape following the granting of a core patent in 2019.
Since its inception, DIANT® has been focused on developing a comprehensive nucleic acid–LNP manufacturing platform. Central to its approach is the utilization of a closed system and an array of process analytical technologies (PATs). The focus has been on consolidation of individual unit operations into one process stream that incorporates not only particle generation but downstream operations, such as solvent removal, buffer exchange, particle surface modification, particle purification, and fill/finish.
DIANT® Technology
DIANT® manufacturing process for producing mRNA–LNPs and other pharmaceutical-grade nanoparticles is built upon a foundational bottom-up approach, employing an ethanol injection strategy combined with single-pass tangential-flow filtration (SPTFF). This innovative technology operates without the need for process solution recirculation, facilitating truly continuous manufacturing. By eliminating numerous batch-based unit operations, the system generates high-quality, repeatable nanoparticles with enhanced confirmation analytics compared with conventional batch processes.
Benefits of the DIANT® continuous nanoparticle manufacturing platform include a smaller production footprint complemented by reduced facility and storage requirements, ready scalability, reduced human intervention, and elimination of holding tanks/times, and it consistently delivers greater particle size control. Moreover, a single set of operators can oversee the entire process, saving time and resources on personnel training. This small footprint, closed system design also reduces costly cleanroom requirements during manufacturing.
The incorporation of inline/online sensors provide users with real-time process data, including temperature and pressure, offering extensive insight into process performance. This enables a high level of process control, allowing operators to monitor the continuous flow of material more closely with DIANT® technology.
The DIANT® continuous nanoparticle technology is based on a single injection site for particle formation. This single “turbulent” jet approach facilitates easy process scaling between lab and GMP manufacturing. Nanoparticles, including LNPs, lipid-based nanoparticles, polymeric nanocarriers, micelles, polymer conjugates, polymer/lipid particles, nanosuspensions, and emulsions, all exhibit consistent characteristics across a range of volumetric flow rates. This feature is highly desirable for risk mitigation over the course of commercial manufacturing runs on the equipment. Additionally, the DIANT® LARU employs the same technology and geometry as the large-scale LiFT system, streamlining the scaling process from R&D to clinical and commercial production, thereby reducing risks, costs and timelines, whether the drug is designed for personalized medicine or a potential commercial blockbuster.
Customizable Mentoring Capabilities
DIANT® technology consistently produces nanoparticles with a precise particle-size distribution; therefore, the process only requires a minimal level of monitoring during operation. For pharmaceutical applications, we recommend incorporating spatially resolved dynamic light scattering (SR-DLS) capability into every system. Additionally, in the context of formulation development, it is ideal to include PAT for monitoring various process and product parameters. This capability allows DIANT® to build out data sets with the integrated PAT, which helps us create a more comprehensive understanding of the nanoparticle-forming process, structure, and characteristics.
Beyond SR-DLS, our systems offer the flexibility to monitor temperature, connectivity, and flow rates. Furthermore, we can integrate UV-visible spectroscopy, chromatography, and other analysis methods as needed to meet the specific requirements of each customer.
Focus on Collaboration and Support
At DIANT®, we prioritize close collaboration with both current and prospective customers to demonstrate the functionality of our technology and its manifold benefits. Our team actively engages with customers’ technical experts to offer tailored support, ranging from conducting feasibility studies and aiding in product development to facilitating process scale-up to the GMP setting. Additionally, we are equipped to integrate new sensors or algorithms as necessary to address specific requirements as needed by our clients.
We stand ready not only to contribute to the further development of customer products but also to assist in devising effective manufacturing and commercialization strategies for our partners.
Maintenance Contracts
We also have a dedicated team of technicians who support the maintenance contracts offered for the DIANT® technology. DIANT® technical expertise is available on demand and will ensure the optimal manufacturing performance of this equipment at our partner’s sites.
Feasibility Services
DIANT® conducts comprehensive feasibility studies involving multiple runs per nanoparticle product, encompassing various formulations. These studies are meticulously designed to yield nanoparticles of optimal size and excellent stability, tailored to the specific properties of the drug substance. Leveraging our extensive expertise in liposomes, LNPs, and polymeric nanocarriers, our technical experts adeptly determine the input parameters that yield the most favorable nanoparticle output for each payload.
Our feasibility services extend beyond mere particle generation. We also concentrate the initially dilute materials produced by the system to attain therapeutically appropriate concentrations and doses. These concentrated samples undergo rigorous analysis using our in-house capabilities to assess particle properties and characterize the encapsulated active pharmaceutical ingredient (API). Animal testing, if required, is conducted by a partner contract research organization or by the customers themselves.
Thanks to our efficient design-of-experiment approach and the high-speed operation of DIANT® equipment (approximately 10X faster than competitors), feasibility studies are quickly completed within a few weeks. This accelerated timeline translates to significant time savings and can often reduce lab time by months, enabling expedited progress in the development process.
Product Development Services
Customers seeking assistance in advancing one or more formulations identified during feasibility studies can leverage DIANT® product development services. This entails a comprehensive exploration of the LNP generation process, beginning with the establishment of a statement of work outlining project goals, milestones, and timelines.
Our product development efforts entail identifying the optimal lipid formulation, typically utilizing multiple specialized lipids and determining their respective percentages. Additionally, we optimize input parameters, such as flow rates, pH, and temperature, to ensure that particles with precise size and lipid composition are generated in a repeatable and scalable manner. Evaluating therapeutically relevant properties of mRNA–LNPs, including bioavailability and efficacy, is integral to this process.
These studies are conducted using our bench-top (LARU) system. Notably, the performance of processes at this scale seamlessly transfers to our high-throughput, large-scale GMP system. This unique approach enables DIANT® to offer a tailored, turnkey solution suitable for both research applications and commercial manufacturing.
Our ability to conduct formulation and process development activities, simultaneously, on the same equipment as is available for use in final manufacturing, sets us apart in the industry. This integrated approach, coupled with our expertise in lipid selection and process scaling and the high-throughput nature of our unique technology magnifies time and cost savings for product development.
We can also offer our partners comprehensive nanoparticle characterization on our in-house equipment. Our technical team can combine an analytical package with our development services that provides our customers with a full understanding of the nanoparticles we produce on our system.
Material Supply Services
Many of our partners also request our experienced team to produce custom nanoparticle material for their preclinical testing needs, such as cell-based assays, toxicity assessments, stability studies, and efficacy evaluations in animal models. The DIANT® team is ready to produce this research-grade material at our in-house clean room and custom-develop this nanoparticle supply for our customers’ needs.
Working Toward Upstream Integration
A core objective at DIANT® is the seamless integration into end-to-end manufacturing and production lines. To achieve this, we’re actively engaged in collaborative development projects with various upstream partners. Given the unique processes of each provider, a feasibility-driven approach is underway to explore diverse avenues for establishing a fully continuous workflow integrated with continuous LNP production. Given the complexity of API (e.g., mRNA) manufacturing, innovative solutions are needed before this goal can be realized.
Many Options for Accelerating LNP Process Development and Manufacturing
DIANT® provides a range of avenues for accessing our services, catering to various customer needs. Some clients come to us with an established formulation and seek product development support exclusively. Others opt to purchase a LARU system and collaborate with our team to conduct feasibility studies and product development work.
Additionally, we closely collaborate with customers who have acquired our system but prefer to handle development independently. In such cases, we ensure they can utilize the equipment to its fullest potential with an easy-to-use interface and on-demand customer service.
Regardless of the chosen approach, all our customers benefit from the compact footprint of DIANT® systems, streamlined operations requiring fewer staff, and efficient acceleration of the development process. These advantages culminate in a seamless transition to GMP production, positioning the DIANT® solution as the ideal choice for advancing nanoparticle development and manufacturing.
A Partner Enabling Efficient and Scalable Nanoparticle Manufacturing for Pharma Applications and Beyond
At DIANT®, we recognize the value of building collaborations and partnerships. We are strategically positioned to support our customers throughout the entire journey, from preclinical development to IND filing, approval, and commercialization.
DIANT® also offers a low barrier to entry with our feasibility and development services. Furthermore, we do not impose licensing fees on customers who do acquire our systems. Instead, our team is confident that, once we’ve developed a refined and scalable process, our customers will continue to leverage DIANT® technology to manufacture their clinical candidates and approved products, enabling us to accompany them throughout the entire product development timeline.Whether the requirement is for LNPs, polymers, or liposomal particles, DIANT® continuous nanoparticle generation technology and our comprehensive product/process development services offer a highly efficient and cost-effective solution. This translates to significant competitive advantages and facilitates the rapid delivery of new medicines, therapeutics, vaccines, and other health products, like nutraceuticals, to those in need. At DIANT®, we are committed to working closely with our customers and partner companies to realize this vision as the next generation of equipment for nanoparticle delivery.