Highly Pure Custom & Catalog Ionizable Lipids for Effective LNPs & Nanomedicines

(CordenPharma Photo) Preparation of an RNA Solution.

In the Q2 Edition of Corden Connect letter, we stressed the importance of a thoughtful and dedicated approach to the effective storage of Lipid Nanoparticles (LNPs), especially when it comes to understanding the stability profiles, degradation pathways and purity levels of ionizable lipids in ethanol, as exemplified in our case study using LP-01, a Novartis lipid. This complex process supports you in navigating the challenges of your RNA delivery.

After the success of our recent LNP Summit in Boston (US), this Q3 edition will focus on the effects of the ionizable lipid selection on the success rate of the LNP formulation and the importance of drug loading to make it effective.

Whether you develop and design your own ionizable lipids or consider licensing catalog ones from the IP owners, both share some common concerns that are critical to choosing your lipid supplier, including target purity, impurity profile, risk assessment, stability, solubility, pH for optimal RNA encapsulation, and RNA-loaded LNP physicochemical properties. For lipids that are custom manufactured, critical considerations include ease of scale up, synthesis steps, purification steps, lipid structure etc.

CordenPharma’s unique position as a leader in catalog and custom lipid manufacturing plays a crucial role in advancing your RNA therapy projects. As a key lipid supplier during the COVID-19 pandemic, and having an established lipid development site since 1987, we bring proven know-how to not only provide the purest lipids available in the market, but also draw upon decades of experience in custom lipid manufacturing to deliver commercial scale ionizable lipids to global markets.

Ionizable Lipid (IL) Selection: Why it matters

These factors must be carefully considered to avoid impacting the RNA-loaded LNP manufacturing workflow.

LNP preparation steps include:

• Step 1: The lipids are individually dissolved and kept in stock solutions, typically using ethanol as the solvent.
• Step 2: In the organic and aqueous phase preparation step, all the lipid components that are essential to making LNPs, such as sterols, phospholipids, and stabilizers, are mixed to prepare the lipid phase, and the nucleic acid of your choice is dissolved in an acidic aqueous phase prior to going into a nanoparticle mixing system.
• Step 3: RNA-loaded LNPs are produced, after which purification and ultrafiltration steps are used to store the nanoparticles.

If your ionizable lipid’s solubility, stability and purity profiles remain unknown during these steps, possible challenges may arise in the further steps, such as the loss of reproducible formulation potency. These barriers to success are widely discussed in the famous paper from Moderna (Packer, M., Gyawali, D., Yerabolu, R. et al. A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems. Nat Commun 12, 6777 (2021)) and a recent paper from the Sanofi mRNA excellence center (Peronin S, Malburet C, Daher-Hassan C, Picard C, Willemin T, Costamagna F, Even L, Eynard T, Bensaid F, Fertier-Prizzon S, Francois-Heude M. Analytical approach for identification and mechanistic insights into mRNA-lipid adduct formation. Mol Ther Nucleic Acids. 2025 Aug 13;36(3):102684).

At CordenPharma, we mitigate those risks in 2 ways:

1. By delivering ultra-pure lipids for those who develop or manufacture their own LNP formulations.
2. If the LNP formulations are made in our Global GMP-Approved (FDA, EMA, PMDA, etc,.) sterile injectable facility, we run intense analytics on your project before manufacturing to avoid any undesired surprises upon scale up and manufacturing studies.

When running analytics for your RNA-loaded LNP formulation, one of the most important factors we monitor is control over drug loading such that it stays unchanged throughout the workflow. This again brings us back to the importance of understanding the lipids which are the backbone of the LNPs. For instance, in a typical LNP formulation, the molar ratio for the lipid components is ionizable lipid 45-50%, cholesterol 37-40%, helper lipid 8-10% and stabilizer 0.5-2%. Challenges that arise at this point include the low presence of the PEGylated lipid over other lipids and drug loading.

To receive the therapeutic impact of the nucleic acid, apart from keeping the genetic cargo’s integrity and purity during the workflow, the total lipid mixture concentration needs to remain in the accepted loss range in order to match the required ionic strength from the nucleic acid to make it stick in the formulation rather than move away and get degraded. Any change in the lipid ratio may indicate a possible change in the formulation composition and material compatibility, weakening the electrostatic binding between the nucleic acids and ionizable lipids, which eventually not only disturbs the drug loading, but may further impact the in-vitro, in-vivo, pharmacokinetics and biodistribution of the RNA-loaded LNP formulation.

CordenPharma’s team of experts in lipid and nanomedicine development ensure your LNP projects are ready to be brought safely and effectively to global markets.

On 9 September we held our inaugural LNP Summit in Boston – the event was a true success! Here’s a video summarizing the summit speakers and their topics – which fostered a lot of exchange about the challenges and important innovations powering the future of nanomedicines.

Learn more about our:

• Lipids and LNP capabilities
• LNP GMP Manufacturing video
• LNP Starter Kits
• Standard Lipid Catalog
• To request a full version of a regulatory white paper, contact our LNP Experts here