Regulatory Considerations for Lipid Excipients

With the explosion of interest in mRNA-based vaccines and therapies following the success of the COVID-19 vaccines has come increased focus on the lipid excipients that enable the delivery of these sensitive nucleic acid molecules, as well as other therapeutic modalities. Successful drug development using these lipid excipients and delivery systems requires close attention to characteristics like purity and safety to comply with complex regulatory requirements analogous to those expected of active pharmaceutical ingredients themselves. MilliporeSigma’s Regulatory Expert Claudia Widmann, Dr.-Ing., and Strategic Marketing Manager for Synthetic Lipids Estelle Beguin, Ph.D., discuss the critical regulatory considerations for these lipid excipients, in conversation with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.

David Alvaro (DA): What can you tell me about how large the RNA development space is right now and the diversity of approaches that might require lipid excipients, including lipid nanoparticles (LNPs), as delivery vehicles?

Estelle Beguin (EB): As you know, there was significant evolution in the mRNA space due to the COVID-19 pandemic. Now, the development of drug delivery systems for nucleic acids is branching out to different programs and different indications. The broadening was particularly noticeable from 2021, but today we really see interesting growth in the development of mRNA therapies for other infectious diseases and in the field of immuno-oncology. Both of those areas will be the next stage. Beyond that, it will be very interesting to see what indications researchers focus on next with respect to mRNA-based systems that leverage LNPs.

DA: While it seems to many as though mRNA drugs and LNPs appeared overnight and just in time to fight COVID-19, they have had a much longer developmental history, correct?

EB: The use of lipids for drug delivery is well established and has been practiced for a very long time. Looking at the delivery of nucleic acids specifically, lipids in the form of liposomes were already being investigated back in the 1970s. Of course, these delivery systems were iteratively improved over time and led to the formulation of LNPs. mRNAs are inherently transient molecules, and this transience is considered an advantage in many therapeutic approaches, because mRNA molecules have a known life span and do not integrate into cellular DNA, and as such they allow for a brief, controlled period of activity. This transience, however, also comes with the fact that these molecules are especially prone to degradation. This is where LNPs can enable both protection of the nucleic acid APIs from degradation and their delivery to the desired site of action.

DA: Is there a standard composition for the LNPs in current use?

EB: There are some standard formulations today, particularly those used for the COVID-19 mRNA vaccines. They have been tested in the clinic and are considered more mainstream at this point. However, there are a wide variety of different formulations for therapies and vaccines currently being investigated in clinical trials. These formulations are not necessarily LNPs, either. Some are lipoplexes that, instead of having four lipid components, have two or three lipid components only. There is much still to be explored for these newer formulations.

DA: Given that need, do you see most mRNA developers staying with those standard formulations in order to follow along a regulatory pathway that has already been established versus exploring novel lipid excipient formulations?

EB: Formulations that have already been proven and approved for use in COVID-19 vaccines can simplify things for drug product developers trying to apply them to other indications. Nonetheless, new formulations will continue to be developed for improvements. There is still much to be proven for these newer lipid delivery systems in ongoing clinical trials, but once candidates get through the different clinical stages, the use of LNPs for other markets will be very much broadened, and companies that are developing these therapeutics will have more options. Either way, the IP landscape in this field is complex, and developers need to be mindful of this to respect the IP rights of third parties.

DA: Given that growing diversity of lipid-based delivery systems for mRNA therapeutics and vaccines, how is the best option selected for a given molecule?

EB: The field has evolved from liposomes to lipoplexes to LNPs. The latter are very much designed for RNA delivery, and, as mentioned, some formulations have already been approved. But LNPs are also complex, with four lipid components, and earlier, simpler options such as lipoplexes can also become attractive options if they can be proven to be effective. Here again, though, much of the development effort still involves formulation screening for that specific application. It is a balance of finding out how to create the least complex formulation that still enables the performance you want.

DA: What can you tell me about the regulatory considerations for the individual lipid components within LNPs and other lipid-based delivery systems?

EB: What drives the need for LNPs in the first place — the instability of mRNA — also drives many regulatory considerations. The fact that mRNA is prone to degradation means that any impurities within the lipid excipients used to encapsulate it should be considered for their impact on the performance of the mRNA overall. Therefore, impurities in lipid excipients must be controlled very tightly and regulatory parameters are very stringent.

Claudia Widmann (CW): That high level of control is also critical because the effect of the API is very much coupled to the lipid excipients. The purity and safety of novel, synthetic lipid excipients must be demonstrated, owing to their central role in the function of the drug product, distinct physicochemical properties, and the potential for interaction with other ingredients or the physicochemical environment. In fact, these excipients must comply with challenging and complex regulatory requirements that are similar to those for APIs.

For this reason, a lipid excipient needs a considerable amount of documentation so that the authorities can understand that everything is under control. It is important, in fact, to demonstrate that the fate and purge of impurities is understood and that the excipient manufacturing process is very much under control to ensure that the lipids produced from each batch have reproducible quality attributes.

DA: In light of the need to control impurities, is it preferable to use chemically synthesized versus naturally derived lipids?

CW: There is a difference. For any excipients obtained from natural sources, it is more difficult to ensure that the same level of product consistency that can be achieved through chemical synthesis can be obtained when using naturally derived materials.

EB: The need to achieve tight impurity control and product consistency makes the synthetic approach advantageous. Unlike with natural materials, synthetic lipids make it possible to know all the impurities involved and to obtain a consistent impurity profile through a well-controlled process. Lipids derived from animal or plant sources could vary in their purity and in the impurities that are present.

DA: Are the regulatory guidelines set at this point, or do they continue to evolve as more is learned about the potential impact of lipids and lipid impurities on mRNA performance?

CW: In general, I would say guidelines are adjusted by regulatory authorities as new information is obtained, because some guidelines and limits are established based on empirical data. One problem, however, is that some jurisdictions don’t have any lipid excipient-specific guidelines. That is why it is so difficult. You have to think very much about what makes sense, what could be a problem, and what might be of concern to regulators. Guidelines for lipid excipients are pretty well established in the United States, but Europe does not have specific guidance documents for lipid excipients. However, the International Council for Harmonisation (ICH) guidelines are a solid lead for the expectations from authorities.

DA: Where these regulations exist, do you feel that the current limits set by regulations are appropriate, or are some too stringent or not stringent enough?

EB: There are some cases where some of the specifications need to be tighter than what is allowed based on the guidance, because those impurities can have an impact on the drug product’s performance. In those cases, our specifications are typically tighter than those found in the guidelines.

One example is residual solvents. The regulatory limits are established on the basis of daily exposure limits for patients. They do not necessarily take into account the impact that solvent impurities might have on the API itself. It is therefore common for drug manufacturers to establish lower limits for these impurities than what are required by the regulations.

DA: What was MilliporeSigma’s role in supporting the manufacture of the COVID-19 mRNA vaccines?

EB: MilliporeSigma offers a broad array of lipid excipients and has extensive expertise in lipid synthesis and manufacturing. I can give you two good examples. The first is the high-purity synthetic cholesterol we developed during the COVID-19 pandemic to meet the need for this important lipid to formulate the novel mRNA vaccines against the SARS-CoV-2 virus. We were able to establish very large-scale manufacturing of that product in record time to support those vaccines, as well as the development of other mRNA-based systems.

A second example would be the supply of ionizable lipids, where we enabled very fast scale-up of production so that sufficient quantities were available to again support the production of the COVID-19 mRNA vaccines. We were able to leverage our extensive network at MilliporeSigma and the flexibility that network offers to push through logistics hurdles, raw material supply issues, and ramp up production to meet demand.

DA: How well was MilliporeSigma already positioned to handle the regulatory challenges that arose during the COVID-19 pandemic?

CW: The entire regulatory group at MilliporeSigma has broad experience with compiling and submitting dossiers and in dealing with more difficult compounds. We are also continually building our knowledge and understanding through each customer project we work on. When you submit the documentation, you may get questions from the regulatory authorities, and this knowledge can be applied during the preparation of the next filing. During the pandemic, application of existing knowledge combined with new learning continued.

EB: I would note that some of the ionizable lipids that we developed for the COVID-19 mRNA vaccines were interesting because they were classified as novel excipients. MilliporeSigma was well-positioned to address this challenge, though, because we have a great team with extensive experience with such novel excipients.

CW: Novel excipients require much more detailed documentation than those with existing monographs in the European or U.S. Pharmacopeias — generally on the same level as that needed for the active drug substance. Additionally, lipid excipients require more detailed information than other excipients, regardless of if they are novel or not. During the pandemic, there was no reduction in the regulatory expectations, because patient safety always remains the top priority. There was, however, tremendous pressure to generate all the data that was required.

DA: For mRNA drug developers looking for a lipid excipient supplier, given the significant regulatory burden, what should be their top considerations when evaluating potential partners?

CW: It is very important for drug product developers to evaluate different lipid suppliers and to work only with those that can ensure consistent and reproducible quality of their products. Physical audits of supplier production facilities are essential to truly understand their capabilities and culture.

EB: I would say there are three major components here. First is the quality of the lipids they provide. Lipids should be high-quality, GMP-compliant, and produced using a highly controlled process. The second is to find a supplier that provides comprehensive support, including having extensive experience with all types of lipid excipients, as well as all the regulatory expertise needed in-house to facilitate compliance and approval.

The third consideration relates to scalability. It is very disruptive if a drug product manufacturer has to change raw material suppliers between preclinical and clinical phases. Switching suppliers can result in differences in the lipid excipients provided, which can result in inconsistencies in the performance of the mRNA drug product. That can be costly, take time, and be very challenging. It is best to work with a supplier that can support drug product developers with lipids suitable for early clinical phases all the way to commercialization.

Claudia Widmann

Claudia Widmann is a Regulatory Expert in the pharma registration group. The main activities are the dossier creation and maintenance for the products, developed on the corresponding location in the subsidiary in switzerland. The product manufacturing is specialized among other products in lipid excipients . Claudia holds a Masters Degree in Regulatory Affairs from the "Technische Universität Lübeck", as well as a Masters Degree and a PhD in a nanotechnological field of expertise.