Dec 08, 2023
July 27, 2023
Genomic medicine is a groundbreaking field that harnesses the power of genetic information to revolutionize healthcare by uncovering crucial insights into genetic predispositions for diseases and drug responses. This information enables personalized medicine approaches, where treatment plans can be tailored to a patient’s specific genetic makeup to develop targeted therapies that offer better outcomes and fewer adverse effects. As technology advances, genomic medicine is poised to unlock new possibilities for precision healthcare and transform how we approach medicine.
The successful application of lipid nanoparticle (LNP) technology is a significant development in genomic medicine and has supported the development of mRNA therapies and vaccines. With the COVID-19 vaccines as a notable example, LNPs have attracted much attention and success in the field of mRNA-based vaccine and drug development. The structure of LNPs typically consists of four components: ionizable lipids, phospholipids, cholesterol, and PEGylated lipids. These components self-assemble into nanoparticles, developing a protective shell around the therapeutic cargo, such as mRNA. The protective encapsulation enables the therapeutic molecules to navigate the body and reach their target cells making LNPs, safe and effective drug delivery systems for various applications, including drug delivery and cell and gene therapy. The LNP technology can fundamentally alter how we prevent, identify, and cure diseases.
Single-Use Technologies Accelerate Genomic Medicine Development Timelines
Speed to market is critical; however, there are difficulties when producing a commercial mRNA-LNP drug product. Single-use technology (SUT) is gaining attention in the field for its ability to facilitate a reliable and robust manufacturing process. It helps maintain a sterile and controlled environment since contamination can negatively impact the safety and effectiveness of LNPs, making it essential to prevent cross-contamination between batches.
Joe Makowiecki, business and product development leader for Enterprise Solutions at Cytiva, says the situation now reminds him of when single-use technology was in its nascency for monoclonal antibody (mAb) manufacture in 2005.
"We had to do a lot of convincing on the benefits of single-use equipment over the existing stainless-steel (clean and re-use) infrastructure. There was a lot of cynicism and questions, like: 'Why would you want to use single-use? What do you do with the plastics that are generated? Does it have the same capabilities as the existing stainless-steel systems? And beyond that, what does it give you that differentiates it?' These were the conversations we were having back then. It was a stainless-steel world, and we were introducing a new paradigm."
Almost 20 years later, the benefits of SUT are well recognized in the manufacture of monoclonal antibodies and biopharmaceutical manufacturing in general. As RNA technology evolves from mRNA to self-amplifying RNA (saRNA) and circular RNA (circRNA) and the encapsulation technologies also become more targeted and complex, Makowiecki says operational flexibility in the manufacturing process will become a prerequisite for RNA manufacturers and that modularized single-use equipment will play a critical role.
The risk of contamination for genomic medicines is a significant concern, leading to loss of therapeutic activity and regulatory delays or rejections because of safety concerns. In addition, RNAse (ribonuclease) contamination from human and animal tissues and microbial sources during sample preparation, RNA extraction, purification, or formulation can lead to the degradation of the RNA. Single-use components, such as disposable mixers, tubing, and filters, minimize the risk of contamination. They also reduce the need for cleaning, maintaining, and validating reusable equipment, benefiting biopharmaceutical companies by decreasing the need for time-consuming and labor-intensive work. In addition to the reduced risk of contamination, enhanced product quality and safety and simplified validation processes help ensure compliance with regulatory requirements, accelerating speed to market.
Cost efficiency is another critical factor driving the adoption of SUT. Although the initial cost of single-use components may be higher than that of reusable equipment, the overall cost-efficiency becomes evident over time. With disposable components, there's no need to invest in equipment cleaning, maintenance, and validation procedures. Additionally, the risk of batch failure and associated downtime is significantly reduced, saving time and money in the long term.
Workflow efficiency is crucial, given the pace at which genomic medicine is advancing. Multi-product and multi-process workflows allow the manufacture of multiple mRNA products in the same facility, and using single-use equipment for cGMP production supports efficient changeover between products. The platform approach of single-use cartridges, such as those found in Precision NanoSystems' NanoAssemblr® formulation systems, accommodates various manufacturing setups for efficient facility utilization across all products and scales.
The use of SUT in mRNA-LNP manufacturing means that extractables and leachables (E&L) are also a consideration, with manufacturers following guidelines such as the United States Pharmacopeia (USP) chapter <665> and the BioPhorum Operations Group (BPOG) protocol for testing of product-contacting plastic components. Testing considerations for mRNA vaccines and therapeutics include modeling exposure based on the dose regime, such as a low-dose regime for a prophylactic vaccine or a high-dose regime for a protein replacement therapy.
Single-Use Technology Supports Scale-up and Scale-out Manufacturing
As the demand for LNPs and mRNA-based therapeutics grows, it is crucial to have a scalable manufacturing process that can quickly adapt to different production volumes. SUTs offer consistent, reproducible performance, minimizing the potential for variability and the risk of batch failure when transitioning from preclinical to GMP manufacturing. SUTs also allow manufacturers to easily scale up or down production volumes by adjusting the number of single-use bioreactors, mixing bags, or other single-use components, unlike stainless-steel equipment which requires a larger investment. This equipment modularity was a significant factor in setting up manufacturing lines across the globe swiftly and efficiently during the COVID-19 pandemic . Also, its advantage in expediting technology transfer, whether new lines are added inside an existing facility or new facilities are established elsewhere, makes SUT an efficient, reliable, and attractive option for manufacturers looking for mRNA-LNP production at various scales.
Precision NanoSystems’ NxGen™ technology empowers its NanoAssemblr® family of products to reproducibly generate optimal particles through a single-use mixer across scales, from the preclinical Ignite™/Ignite+™ and Blaze™/Blaze+™ platforms to the clinical and commercial systems. The NanoAssemblr® commercial formulation system is an automated, single-use system for the clinical and commercial production of lipid nanoparticles (LNPs) under cGMP conditions. The single-use flow path minimizes the need for sanitizing and performing cleaning validation, enabling efficient changeover between production runs while minimizing the risk of cross-contamination, and supporting multi-product manufacturing in GMP facilities.
With the systematic development of new technologies, SUT provides a flexible and adaptable platform for integrating these innovations quickly. By adopting single-use technologies and platforms into their workflows, biopharma manufacturers can reduce the time required for facility setup, cleaning, and validation, enabling faster turnaround times and accelerating the production of mRNA-based vaccines and therapeutics.
Learn more about the unique challenges and risks in each regulatory stage of the LNP drug development process in the whitepaper The Fundamentals of Developing mRNA Therapeutics.
1. Bown CP, Bollyky TJ. How COVID-19 vaccine supply chains emerged in the midst of a pandemic. World Econ. 2022 Feb;45(2):468-522. doi: 10.1111/twec.13183. Epub 2021 Oct 28. PMID: 34548749; PMCID: PMC8447169.
Dec 08, 2023
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