August 15, 2022 PAO-07-022-CL-04
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.
lipid components only. There is much still to be explored for these newer formulations.
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.
a balance of finding out how to create the least complex formulation that still enables the performance you want.
egradation 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.
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.
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.
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.
MilliporeSigma and the flexibility that network offers to push through logistics hurdles, raw material supply issues, and ramp up production to meet demand.
consistent and reproducible quality
ncluding 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 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.