LIPID SOURCING & SELECTION - Navigating the Lipid Landscape: Overcoming the Challenges of Lipid Sourcing & Selection for LNPs

INTRODUCTION

Lipid nanoparticles (LNPs) represent one of the most signifi­cant advances in drug delivery technology in recent decades. Gaining prominence during the COVID-19 pandemic as the de­livery vehicle for mRNA-based vaccines, LNPs have since attracted significant interest and investment, and their potential has never been more apparent.

LNPs offer numerous advantages that make them increas­ingly valuable in modern medicine — from safe and effective de­livery of nucleic acid cargo to cell-free manufacturing processes and ease of production scale-up. But the path to developing suc­cessful LNP-based therapies and bringing them to market is far from straightforward.

Perhaps one of the most significant challenges lies in select­ing and sourcing the molecules at the heart of LNPs: lipids. Lipids can impact anything from particle size and encapsulation effi­ciency to circulation time and cellular uptake. The right choices can optimize stability, efficacy, and scalability, while the wrong ones can introduce roadblocks that are difficult (and costly) to overcome. Even small variations in lipid composition can lead to significant functional changes in LNPs; selecting and sourcing the right lipids can therefore be highly complex and present numer­ous challenges.

So what are the biggest pitfalls in lipid selection and sourc­ing, and how can developers begin to navigate them?

 THE HIDDEN CHALLENGES OF LIPID SELECTION

The therapeutic success of an LNP formulation depends on choosing the right combination of lipids. Each lipid serves a dis­tinct and critical role in the LNP complex, and the performance of an LNP formulation is directly tied to the composition and characteristics of the lipids it contains. The importance of the lipid se­lection process, then, cannot be overstated.

However, navigating the vast landscape of lipid options re­mains a complex and difficult task. There are a handful of lipids used in LNP-formulations, including cationic lipids, ionizable lipids, phospholipids, sterol lipids, and PEGylated lipids. Each lipid type is associated with a unique set of challenges and limi­tations, which must be carefully balanced with its advantages.

Some lipids, particularly cationic lipids, have largely fallen out of favor due to issues with toxicity and immune activation pre­senting serious safety concerns. However, even lipids that are well-established in LNP systems can present developmental chal­lenges that can impact formulation performance and long-term viability.

Take PEGylated lipids, for instance. These lipids are widely used in formulations and, despite comprising the smallest per­centage of lipid components in LNPs, they play a vital role in in­creasing circulation time, improving steric stability, and modulating size. However, due to their amorphous structure, syn­thesizing PEGylated lipids is inherently difficult. When synthesis isn’t carefully controlled, it can lead to a broad distribution of PEG molecule chain lengths — a factor that can impact LNP structure and function. This variability becomes a major concern when scaling up the manufacturing process, as it can be challenging to maintain batch-to-batch consistency and requires considerable expertise and experience in lipid synthesis and charac­terization.

Beyond structural and manufacturing difficulties, lipid selection is also impacted by legal and commercial challenges. Ion­izable lipids, for example, are widely used for their ability to change their charge based on the pH of their environment — being neutral at physiological pH but pos­itively charged in more acidic conditions — making them extremely valuable in the LNP complex. Serving a multifunctional role in supporting nucleic acid complexa­tion and endosomal release, they are con­sidered a safter alternative to cationic lipids.

But, while these characteristics are de­sirable, using ionizable lipids in LNP for­mulations means developers must navigate an intellectual property (IP) “minefield.” The ionizable lipid IP land­scape is crisscrossed with broad and vague patents that make it difficult to cre­ate a novel version without other compa­nies claiming infringement. It is easy for large, well-funded organizations to tie up smaller ones in legal costs — even if the supposedly infringing company’s ionizable lipid is truly novel.

Because the vast majority of ionizable lipids currently used in commercial thera­peutics are already patented, unless devel­opers want to pay a licensing fee, they will need to customize these lipids. This brings fresh challenges around adherence to strict regulatory requirements and de­mands significant time and resources. De­velopers looking to create their own customized ionizable lipids should there­fore consult both chemistry and legal ex­perts who are deeply familiar with the space and start planning early to minimize program delays and disruption.

Beyond ionizable and PEGylated lipids, additional components like phos­pholipids and sterol lipids can also present unique challenges. Phospholipids, often referred to as “helper lipids,” play a fun­damental role in promoting structural in­tegrity and modulating membrane fluidity and endosomal escape. However, despite their importance, there is a shortage of commercially orientated expertise in this space, making it difficult to find a manu­facturer that can synthesize phospholipids for LNP therapeutic applications. In the case of sterol lipids (such as cholesterol), the challenge lies in selecting the source of the molecule, with synthetic cholesterol of­fering fewer safety concerns and regula­tory issues than mammalian and plant-derived cholesterol.

Ultimately, choosing the right lipids isn’t only about their functional perform­ance within the LNP — it’s also about un­derstanding the regulatory, legal, and manufacturing implications that come with them. Making the right choice requires a deep understanding of the lipid land­scape, from the intricacies of lipid chem­istry to the complexities of LNP IP.

PURITY MATTERS: A CRITICAL HURDLE IN LIPID DEVELOPMENT

Even when the right lipid has been identified, success depends on the ability to produce it consistently at a high stan­dard of purity. Lipid purity is a non-nego­tiable factor in LNP formulation, as even small levels of impurities can introduce safety risks (through toxicity or immuno­genicity) and impact LNP formation, sta­bility, and biological activity. While it is possible to consistently create lipids with >99% purity with the right expertise and quality assurance systems, it is far from easy.

As every lipid is structurally different, the purification process must be specifi­cally refined and tailored to each one — a costly and time-consuming process that requires highly specialized expertise. And as production scales up, so do the chal­lenges. Purification methods that work at milligram or gram scale don’t often trans­late cleanly to kilogram-scale production, requiring further refinement. Moreover, not every facility is equipped with the special­ized equipment needed to support large-scale lipid purification, such as large chromatography columns, which are not universally available.

Part of the challenge of purification lies not in the process itself but in the analysis. Due to their structural diversity and lack of chromophore, standard meth­ods of purity analysis aren’t sufficient, and manufacturers must rely on more ad­vanced analytical techniques. As with the purification process, the analysis must be tailored to each individual lipid, making this a time-consuming task in its own right.

Ultimately, achieving cGMP-grade lipids at scale is not a trivial undertaking. It requires a purpose-built quality system, a deep bench of expertise, and a clear un­derstanding of how purification and ana­lytical methods must be adapted to manufacturing at scale.

THE STRATEGIC CHALLENGE OF SOURCING LIPIDS FOR LNPS

Moving from early stage LNP formu­lation to commercial production requires companies to strategically plan their lipid sourcing. Even when the ideal lipid struc­ture has been identified and a repro­ducible purification process is in place, success ultimately depends on the ability to source that lipid consistently, at scale, and in compliance with regulatory stan­dards. For developers, this can represent persistent challenges that must be ad­dressed strategically to avoid delays, added costs, or formulation setbacks.

Initial Lipid Optimization
In early LNP development, only small quantities of lipids are required for screen­ing and optimization, meaning that devel­opers can use research use only (RUO) grade materials sourced from a suitable partner. At this stage, it can be difficult to manage costs as small quantities typically carry price premiums; additionally, finding lipid suppliers with the technical expertise and capacity needed to troubleshoot and optimize formulations can be challenging. This is especially true when working with customized lipid structures, where more specialized knowledge may be required.

Maintaining Continuity: From RUO to cGMP
One of the earliest stumbling blocks in lipid sourcing is the transition from RUO materials to the larger quantities required for clinical trials. Many suppliers only offer RUO-grade products, leaving developers with no choice but to switch vendors mid-program — a move that introduces uncer­tainty, potential performance changes, and costly revalidation.

To avoid this disruption, teams can look to engage suppliers that offer both RUO and cGMP versions of the same lipid early in the development process. This continuity not only helps streamline the transition into clinical phases but also reduces risks of LNP formulation inconsistencies.

Planning for Scale
Moving from the small quantities required in early stage studies to the larger quantities needed for clinical and commercial production presents another difficulty. Clinical programs typically need cGMP-grade materials in multiple grams to kilogram quan­tities — something that not all suppliers are equipped to handle. Producing high-quality, cGMP-compliant lipids at scale requires manufacturers to operate cGMP-certified facilities, which must meet extensive regulatory requirements and maintain thorough documentation.

To consistently produce cGMP-grade materials at scale, sup­pliers must have robust quality assurance systems. It is therefore essential to thoroughly evaluate supplier facilities and quality processes when moving into large-scale production. Identifying partners with proven capabilities early on can help developers avoid costly delays, revalidation work, or reformulation further down the line.

Anticipating Potential Delays
Lead times for high-purity, cGMP-grade lipids can stretch for months, making the transition from early research to large-scale production both time-sensitive and operationally challenging. Any delays can put pressure on timelines and increase the risk of pro­gram disruption. To mitigate this, developers should engage with lipid suppliers as early as possible and proactively plan for their scale requirements. Working with lipid providers who have ex­pertise in lipid synthesis and analytical development — and who support programs across all stages — can significantly reduce timelines and minimize disruption when moving between phases.

BUILDING THE FOUNDATION FOR LNP SUCCESS

Lipid selection and sourcing are not only matters of function and convenience, they are strategic decisions that must consider scalability, regulatory demands, and commercial viability from the start. Each choice, whether related to lipid structure, purity, or supplier, can have far-reaching implications across the entire LNP lifecycle.

Success depends on selecting lipids that not only perform ef­fectively within the formulation, but are also free from legal red tape, can be purified to a high standard, and sourced reliably at scale. For developers looking to create a novel LNP therapeutic, failing to anticipate or fully recognize the challenges of lipid se­lection and sourcing can create delays, increase costs, and po­tentially derail otherwise promising programs.

Effectively navigating the complexity of the lipid landscape requires not only deep industry expertise, but the strategic fore­sight to align scientific, legal, and manufacturing requirements from the very beginning.

Dr. Donald Kelemen is Chief Scientific Officer at ABITEC Corporation, a global leader in lipid chemistry and formulation technologies for pharmaceutical and nutritional applications. He oversees the development of high-purity lipids and custom excipients that support a wide range of advanced therapeutic platforms, including lipid nanoparticles (LNPs). He earned his PhD in Nutrition and Biotechnology and has more than 20 years of experience in the pharmaceutical industry.