May 6, 2023 PAO-04-23-CL-05
In the heavily regulated pharmaceutical industry, it takes many years for molecules with promising biological/therapeutic activity to become approved and marketed drug products. In addition, once a product is commercialized, it is very difficult to change the approved manufacturing process. Since batch processing was the conventional and established method, this approach is widely accepted from the perspectives of both drug developers and regulators, and the pharmaceutical/biopharmaceutical industry has been slower to widely adopt continuous processes compared with other manufacturing industries.
Transitioning to continuous manufacturing processes has been difficult for drug developers given concerns over regulatory acceptance and impacts on timelines. In the view of many drug developers and manufacturers, it is far less risky to use proven and well-understood technologies and strategies that do not carry the potential for delays in new drug approvals or, in the worst case, rejection by regulatory authorities.
In addition, continuous processing requires real-time collection of analytical data and sophisticated systems for immediate analysis of that data to continuously provide monitoring of critical process parameters and feedback for ongoing process control. The development of more advanced inline and online process analytical technologies (PATs) and hardware/software data management and processing solutions that were previously unavailable or not sufficiently robust for large-scale manufacturing has thus been a recent and transformative driver of the adoption of continuous manufacturing.
Real-time monitoring of continuous processes ultimately allows for considerably greater control of manufacturing processes than is possible in batch manufacturing mode. Typically, continuous processes involve much smaller volumes that interact for much shorter periods of time. These attributes — combined with real-time monitoring via PATs — results in a higher degree of control that minimizes undesired reactions and many of the complications.
Greater control, in turn, avoids most of the inherent complications associated with scale-up of batch processes and leads to more efficient and straightforward process scalability. Unlike batch processes, for which scale is achieved by increasing volumes within a reactor, a continuous process can provide more product if run for a longer period of time or if the volumetric flowrate is increased without changing the volume in reaction. Because of the high level of process control, consistent product quality is achieved throughout longer runs. For continuous processes involving ultra-small volumes, such as those implemented using tiny microfluidic devices with restricted volumetric throughput, scale can be achieved by running multiple processes in parallel.
Another recent driver for the adoption of continuous manufacturing in the pharmaceutical industry has been the Food and Drug Administration (FDA). The agency has been pushing for the introduction and adoption of advanced manufacturing technologies that improve quality and consistency while reducing costs, notably including an emphasis on continuous processing. Through various advanced manufacturing initiatives, grants and awards have been established for the development of transformative continuous manufacturing solutions. In the end, therefore, the combined efforts of industry and regulators have led to the recent emergence of a range of continuous manufacturing approaches, including the technology that DIANT Pharma has developed for the production of many types of nanoparticles, such as lipid nanoparticles (LNPs) encapsulating oligonucleotide (e.g., messenger RNA (mRNA)) therapeutic and vaccine actives, which have recently seen significant growth in demand across the industry.
Current continuous processing solutions allow for a significant reduction in the number of unit operations needed for drug substance and drug product manufacturing. When deployed in combination with advanced automation technologies and platforms, the personnel (and associated training time) required to operate these continuous processes is much less than that needed for batch processes, and fewer touchpoints of human interaction additionally reduces risks of human error and contamination of the processes. Hold and storage times are eliminated, leading to smaller plant footprints. The smaller volumes and dramatically shorter residence times also enable the production of molecules that cannot be safely manufactured in batch mode, creating opportunities for the development of truly novel drug substances not previously possible.
The ultimate — still aspirational — goal for the future of biopharmaceutical manufacturing is true end-to-end, integrated continuous processes in which raw materials are fed into the process on one end and the final, formulated drug product is generated at the other, with all intermediate operations linked together. For mRNA–LNP products, that would mean production of the mRNA (including plasmid manufacture linked to in vitro transcription and purification steps) using a continuous process that is then directly linked to the LNP processing stream, which would be connected to continuous lipid production streams as well and would include all downstream operations through final drug product formulation and fill/finish. The concept could be taken even further, with raw materials from petroleum plants connected into the upstream side, where appropriate.
At this stage, however, most continuous processes involve linkage of a limited number of unit operations because the technology is still lacking for full implementation of end-to-end solutions. For mRNA–LNP production, one bottleneck is sterility and endotoxin testing, as there is no inline/online analytical method currently available, and testing must be performed offline. That limitation presently prevents implementation of an integrated, end-to-end process through final formulation and fill/finish but points the way toward forthcoming innovation that can help realize that vision.
Top-down and bottom-up approaches have both been used to generate nanoparticles. In the top-down approach, the material is generated in bulk by some means, such as extrusion. It is then subjected to a process (e.g., nanomilling) that reduces the particle size of the material to the nanoscale, which is followed by particle-size analysis.
The bottom-up approach typically involves solvent (usually ethanol) injection into an aqueous solution of the material. For LNPs, the ethanol is injected into an aqueous solution containing the relevant lipids. A second step involves concentration and removal of the solvent.
From this point forward, the two approaches converge. Depending on the ultimate product formulation, further manipulation of the nanoparticles may or may not be required, potentially along with a subsequent purification step. The need to test the material after each unit operation requires not only time but also holding/storage tanks. The final step for pharmaceutical applications involves sterile filtration and bioburden reduction.
Overall, typical batch processes therefore comprise anywhere from six to nine unit operations. With continuous nanoparticle generation, it is possible to fold all of those unit operations into a single process within a closed system.
The goal at DIANT Pharma has been to integrate the separate unit operations required for nanoparticle generation into one continuous process or at least a single closed system. The successfully established process builds on the basic bottom-up ethanol injection strategy through use of single-pass tangential-flow filtration (SPTFF). This technology does not include any recirculation of the process solution and thus enables truly continuous operation for extended periods of time.
As with other continuous manufacturing solutions, DIANT Pharma’s technology for the production of mRNA–LNPs and other pharmaceutical-grade nanoparticles offers the benefits of a smaller production footprint complemented by reduced facility and storage requirements, ready scalability, reduced human intervention, elimination of holding tanks/times, and — specifically for this process — greater particle size control. In addition, only one set of operators is required to run the entire process, saving time and money on personnel and personnel training. Furthermore, because the system is fully closed, cleanroom requirements are also reduced.
We view our approach as truly revolutionary rather than evolutionary. It represents a unique solution for nanoparticle generation and has the potential to change the way in which this process is implemented in the pharma industry, including but not limited to the production of mRNA–LNPs with therapeutic and vaccine applications.
DIANT Pharma’s continuous nanoparticle generation system not only eliminates numerous batch-based unit operations, it also generates very high-quality nanoparticles with improved properties compared with those typically obtained from batch processes. The inline/atline sensors incorporated into the system provide real-time process data (e.g., temperature, pressure) throughout the entire process. As a result, users have extensive insight regarding process performance and the ability to understand what is happening during the continuous flow of material, which allows a high level of process control.
DIANT’s system, which is based on a single injection site for formation of the nanoparticles, is designed to enable easy process scaling. Nanoparticles generated over a range of volumetric flow rates have similar characteristics, making this solution highly desirable from a risk-mitigation perspective. In addition, the lab and research unit (LARU) uses the same technology and geometry as the large-scale system, eliminating the need for extensive process optimization when scaling up from R&D to clinical and commercial production.
As importantly, the technology can be used to produce a variety of nanoparticles. In addition to LNPs and other lipid-based nanoparticles, polymeric nanoparticles, polymeric micelles, and other polymer conjugates, DIANT’s system can also generate polymer/lipid particles, nanosuspensions, and nanoemulsions. All but the nanoemulsions can be produced using the exact same system setup used for the production of LNPs. The only changes required would be due to chemical compatibility issues. For the production of nanoemulsions, some front-end modifications are required to accommodate oil-based (rather than alcohol-based) solvents and their different viscosities and required operating temperatures. Both options are currently commercially available.
Given that the continuous production of nanoparticles is a new concept in the pharmaceutical industry, DIANT Pharma is committed to working closely with our customers — and potential customers — to explain and demonstrate how our technology works and the numerous benefits it provides. We are not interested in simply selling equipment — we want to be involved with our customers to the greatest extent possible to help enable further innovation on their part.
Companies interested in learning more about DIANT’s continuous production solution often first send us material to be processed so that they can evaluate the properties of the products generated using the system. We welcome the opportunity to build those relationships and help them better understand and appreciate the technology.
Once a company acquires the DIANT Pharma system, we collaborate with the customer’s technical experts to provide as much support as they require, including assisting with the performance of feasibility studies, product development, and process scale-up. We are ready to help further develop customer products, as well as manufacturing and/or commercialization strategies. Our efforts may include integration of new sensors or algorithms to meet their specific needs. We want customers, regardless of size, to get to know and trust us and truly understand who we are and the value we provide through not only our unique manufacturing system but our expertise and collaborative culture.
Antonio Costa, Ph.D. is chief executive officer at DIANT Pharma Inc., an early-stage company that provides continuous manufacturing technology, and an assistant research professor at UConn in the Pharmaceutical Sciences department. His work focuses on continuous manufacturing approaches, downstream processing of nanoparticle formulations, physicochemical characterization, process analytical technology integration and systems engineering. He is an author on 12 peer-reviewed publications and inventor on two granted patents and six patent applications.
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