mRNA-LNP Vaccines Spur Global Dialogue on Nanomaterial Standards and Regulatory Approaches


The successful development of mRNA-lipid nanoparticle (LNP) vaccines to address the COVID-19 pandemic has highlighted the power of nanoparticle-based formulations in producing safe and efficacious medicinal products.

The mRNA-LNP system comprises part of a broader pharma trend of utilizing nanotechnology and “functional excipients” in medicines to improve efficacy, bioavailability, dose–response, targeting ability, personalization, and safety. In this case, the lipid nanoparticles in the delivery system form a protective shell around the mRNA, and are crucial for the cellular uptake, endosomal processing, and release of mRNA in vivo.  

However, the development of nanomedicines, which may deploy novel/functional excipients and impact traditional excipient/API definitional boundaries, are also associated with significant challenges in their manufacture, characterization, and quality control.

Considerable global efforts are being made to facilitate the discussion between manufacturers, regulators, pharmacopeias, academics and contract labs on these challenges in an effort to establish appropriate best practices, standards, guidance, and regulatory approaches.

The story that follows is divided into five parts, reflective of the industry, regulator, and compendial vantage points on these issues.

● Part I: Pfizer/BioNTech Lipid Challenges with mRNA-LNP COVID Vaccine

The Pfizer/BioNTech mRNA vaccine Comirnaty uses four different lipid excipients, two of which are considered “novel.” At the May 2022 IPEC-Americas “Excipient World” conference, Pfizer’s Roger Pak outlined the complex journey involved in using the lipids to develop Comirnaty.

Pak described the multiple challenges involving the supply chain, comparability, analytics, specifications, and regulation and the steps taken to overcome them against the backdrop of a global pandemic with accelerated timelines and social distancing.

Part II: FDA’s Novel Excipient Review Pilot Program and Nanomaterials Guidance

The second part of the story focuses on two FDA initiatives to support excipient development and innovation:

A pilot program through which FDA offers a pathway to pre-review novel excipients independently from the drug application process was launched by CDER in September 2021. A panel discussion at the IPEC conference afforded FDA an opportunity to provide an update on the program’s status and for panelists to provide insights on the engagement of the IQ Consortium, IPEC-Americas and USP with novel excipient issues.

In April 2022, FDA released a final guidance on drug products that contain nanomaterials. The story focuses on the discussion in the guidance of excipients, which appears within the quality recommendations section, and on the changes made to the original draft issued in December 2017, including the addition of a glossary. [A list of IPQ stories on the novel excipient dialogue over the past decade is included.]

Part III USP Draft Guideline and Other Efforts on mRNA Vaccine Quality

Part three considers the recent formative USP draft guideline on analytical procedures to support mRNA vaccine quality, which provides specific detail on quality attributes and test methods.

In focus is the presentation by USP’s Diane McCarthy at an August 2022 conference on bioprocessing, in which she outlined the content, status, stakeholder input on and future directions of the mRNA vaccine guideline. She also described other USP initiatives in support of COVID-19 vaccines, including a USP vaccine quality assessment “toolkit.”

● Part IV: The EDQM Nanomedicines Dialogue and WHO on Regulating mRNA Vaccine Quality

Part IV shifts to the European and global vantage point. Reviewed are the discussions at an EDQM conference in Strasbourg, France in June 2022, which focused on Ph. Eur. nano-related activities and the role the pharmacopoeia should play in addressing the quality requirements for nanomedicines.

Included were presentations by Moderna and Precision Nanosystems on the CMC considerations for mRNA-LNP vaccines. Other nanomedicines of therapeutic interest were discussed during the second day of the conference, which concluded with an interactive session on the future of nanomedicines and how the Ph. Eur. can best support their quality.

Also discussed in Part IV is the substantial contribution WHO has made in the mRNA vaccine quality/CMC arena with the publishing in late 2021 of guidance on the “regulatory considerations” involved in their evaluation. The “technical document” appears as Annex 3 of the informative April 2022 technical report from the WHO Expert Committee on Biological Standardization. The most extensive section of the 60-page annex is that on mRNA vaccine manufacture and control.

Part V: Potency Assays for mRNA-LNP Vaccines

The final part of the story addresses the discussion of the unique challenges in developing potency assays for mRNA-LNP vaccines that took place at the July CASSS CMC strategy forum and bioassays meeting that followed.

Pfizer’s Emma Reyes addressed the development, optimization, and validation of an in vitro expression potency assay, which uses flow cytometry for data analysis. The assay was demonstrated as suitable for COVID-19 variants of concern and has now been implemented globally by Pfizer for routine product quality control testing of its mRNA-LNP vaccine products.

Merck’s Nicole Smiddy highlighted the company’s development of a high-throughput cell-based assay for measuring mRNA-LNP vaccine potency. The highly automated process allows the assay to be used as a rapid screening tool in vaccine formulation, processing, and manufacturing.

[Editor’s Note: A five-part story released by IPQ on November 18, 2021 provides insights from industry COVID vaccine project leaders – including those leading the Pfizer/BioNTech and Moderna mRNA-LNP projects – on: how their companies managed to address the daunting development, manufacturing, and supply chain challenges involved in delivering a vaccine in unprecedented speed during a pandemic, and ● the lessons that can be garnered from that experience in moving forward.]

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