(CordenPharma Photo) Lipid development at CordenPharma.
RNA-based therapies are emerging as a transformative class of treatments that are changing the landscape of medicine. Recently, these therapies have been successfully developed into clinically approved options, positioning them as one of the most promising technologies for preventing and treating a variety of diseases. A notable milestone was achieved in 2018 with the approval of a small interfering RNA (siRNA) therapy (Onpattro®) for the treatment of polyneuropathy in patients with hereditary transthyretin-mediated amyloidosis (hATTR). More recently, messenger RNA (mRNA) vaccines, such as those from BioNTech/Pfizer and Moderna, have been rapidly developed to combat COVID-19.
The successful clinical translation of RNA therapeutics largely depends on the effectiveness of the drug delivery system known as Lipid Nanoparticles (LNPs). LNPs serve several important functions: they protect RNA from degradation, deliver it to targeted cells and tissues, and facilitate its internalization by the cells, ultimately ensuring that it reaches the cytosol. While LNPs work to overcome various biological barriers, it is essential for them to be low in toxicity and immunogenicity. This important role of LNPs makes it necessary to design them carefully and tailor them to the therapeutic application of the choice.
Achieving a safe, reproducible potency and a highly stable drug product formulation involves not only the quality of the active ingredients but also the role of excipients. While nucleic acids often take the spotlight due to their therapeutic functionality, the effectiveness of these treatments also depends on the quality of the delivery vehicle. If the vehicle used to carry the payload is inadequate, the nucleic acids may not reach the specific organelles where they can have a therapeutic effect.
LNPs and their components can experience physical and chemical degradation during storage, and these processes are accelerated by thermal stress. To mitigate these risks, mRNA/LNP formulations are currently stored at temperatures of −20 °C or lower. This challenge forces RNA-LNP therapeutic developers to investigate even more about the individual characteristics of lipid components used in their formulations.
Solubility, stability, and lipid handling can differ for each lipid compound that is used to create LNPs. Of the four components that generally comprise the LNP, it is the ionizable lipid component that binds to the nucleic acids electrostatically, which has a big impact on drug loading. This is why sourcing high-quality ionizable lipids is an important step in achieving good encapsulation efficiency.
Additionally, it is critical to pre- and post-characterize the nucleic acids to maintain an unchanged quality throughout the manufacturing process to protect the purity, integrity, identity, or stability of the nucleic acids, which in turn directly impacts the potency of the formulation.
Why quality matters
The integrity of lipid components plays a critical role in the performance and reproducibility of LNP formulations. Variability in lipid by‑product profiles, whether due to batch-to‑batch differences or diverging supplier standards, can compromise formulation consistency and even deactivate the RNA payload. To avoid such pitfalls, it is essential to use high quality lipids from early-stage development through to clinical applications.
At CordenPharma, we ensure rigorously controlled lipid production by applying Quality‑by‑Design (QbD) principles across every stage. By starting with high-purity raw materials, employing highly efficient synthetic routes, and leveraging our decades of expertise in lipid purification, we consistently deliver high quality lipid products. Our advanced analytical technologies further guarantee that every batch meets the stringent standards demanded by xRNA, gene, cell therapy, and vaccine innovators.
Key considerations when sourcing raw materials – such as an ionizable lipid for LNP formulation – are the quality and method to assess their purity. To underscore this, our Lipid Development Team conducted a case study focused on a Novartis ionizable lipid called LP-01.
Using (U)HPLC coupled with high-sensitivity Charged Aerosol Detection (CAD) – a universally applicable, state-of-the-art analytical technique ideal for ionizable lipids – we evaluated LP-01 samples from six different vendors across the United States, Europe, and Asia, including our own. In a first step, although all suppliers claimed ≥97% purity, our data revealed significant discrepancies. In particular, the results demonstrated that CordenPharma’s LP‑01 consistently achieved the highest purity levels, thanks to state-of-the art analytical methodology combined with our Quality-by-Design development approach (Graph 1).
(CordenPharma Graph 1) Evaluation via HPLC-CAD of the purity of various
LP-01 ionizable lipid excipients compared with the one developed by CordenPharma.
Purity = quality?
Maintaining high purity is essential for robust and reliable manufacturing of an ionizable lipid. However, even when only 1% of compounds remain, it’s vital to understand those trace impurities and their degradation pathways to ensure no critical by‑products arise. By coupling (U)HPLC‑CAD with mass spectrometry (MS), our team successfully identified and structurally characterized these by‑products – tracing their origins to specific stages of synthesis and storage (Graph 2).
(CordenPharma Graph 2) By-products of the analyzed LP-01.
But how can one make sure to have reproducible, highly stable formulations?
To investigate that, the R&D team went one step further and evaluated the stability of our LP-01 ionizable lipid at 10 mg/mL concentration in solution at various temperatures. For example, we have evaluated the stability of an ethanol solution of the ionizable lipid LP-01 at -20°C, +4°C, and ambient temperature to define suitable storage conditions of the solutions (Graph 3), as well as gain an understanding of the degradation products (Graph 4).
(CordenPharma Graph 3) Stability of LP-01 in EtOH at different temperatures.
(CordenPharma Graph 4) LP-01 degradation products.
At the cutting edge of lipid manufacturing, we combine scientific rigor with extensive industry experience to deliver materials of the highest quality. This begins with sourcing ultra-pure starting materials and minimizing naturally occurring isomers, then extending to a Quality‑by‑Design (QbD) framework that anticipates and controls critical by-products. Our precision-driven processes rely on sophisticated analytical platforms, such as HPLC‑CAD and MS, to guarantee peerless purity.
Even trace impurities in ionizable lipids can bind RNA payloads and compromise potency or safety. That’s why we treat our lipids with the same diligence as APIs. Drawing on decades of expertise, resilient supply chains, and cutting-edge development capabilities, we bring reliability and excellence to every stage of lipid production.
Finally, we leverage CordenPharma’s deep proficiency in lipid characterization and manufacturing to support innovators in bringing their therapeutic drug products to global markets swiftly and with uncompromised quality. From backward integration with custom, ultra-pure ionizable lipid manufacturing to forward integration into sterile injectable drug product services, we offer a truly integrated, end-to-end solution that de-risks impurity challenges and ensures seamless development and delivery for our clients.
Watch our LNP GMP Manufacturing video or contact us here for further information on LNP projects.
Note – this article is co-authored by:
Dr. Uwe Albrecht, Senior Expert in Lipid Development, CordenPharma Liestal
