Promising mRNA tech comes with regulatory, CMC headaches
As the buzz builds around messenger RNA (mRNA) technology’s use for two leading Covid-19 candidates, manufacturers and regulatory professionals are facing facts: This is not simple technology.
Complex manufacturing processes, delivery vehicles that must be treated more as drug substances than excipients, and potential immunogenicity headaches are among the challenges industry faces as this promising technology is harnessed to address an increasing number of health conditions.
At October’s virtual Euro Convergence conference, Tracy Meffen, VP for quality and regulatory affairs at Genevent Sciences Corporation, walked attendees through the basics of the technology, placing focus on chemistry, manufacturing and control (CMC) considerations from a regulatory affairs perspective.
Two types of RNA therapeutics work in different ways to create opposing effects, explained Meffen. By carrying genetic information in single-stranded RNA that enables protein synthesis, mRNA therapeutics up-regulate proteins that are faulty or missing. In contrast, the double-stranded RNA strands of siRNA therapeutics degrade mRNA after transcription, thereby preventing translation and eliminating excessive proteins that cause disease because they are faulty or overabundant.
Messenger RNA is considered by both the FDA and the EMA to be gene therapy “even though RNA does not interact with the genome,” said Meffen in giving a regulatory overview of the two types of RNA therapies. However, mRNA, which is regulated by the FDA’s Center for Biologics Evaluation and Research (CBER) is not yet classified as a regenerative medicine advanced therapy (RMAT). EMA considers mRNA to be an advanced therapy medicinal product (ATMP).
Neither FDA nor EMA consider siRNAs to be gene therapy. “FDA regulates them as a drug, not a biologic, and they are not an ATMP,” explained Meffen; siRNA therapies do not have RMAT status. For both types of RNA therapies, sponsors should be aware of the variety of regulatory programs available for rare genetic disorders, she noted.
In terms of the nuts and bolts of RNA therapeutics, the key barrier is delivery; getting both mRNA and siRNA across the cell membrane is challenging. Two ways that have been developed to achieve delivery are the use of lipid nanoparticles (LNPs) to envelop the nucleic acid — a technique that can be used with both types of RNA therapeutics — and using N-acetylgalactosamine (GalNAc) linker chemistry to stabilize siRNA and enhance cellular delivery. While the lipid nanoparticle technology is being used for mRNA Covid-19 vaccine candidates, “A key advantage of the GalNAc technology is that it can be used to inject siRNA subcutaneously,” said Meffen.
Potential clinical applications for the two RNA therapeutics abound; mRNA is being investigated for vaccines against other viruses in addition to Covid-19, as well as for cancer vaccines and rare genetic disorders including cystic fibrosis. On the siRNA side, ongoing research is looking at the technology for hepatitis B virus treatment, and for a variety of rare genetic disorders. The first two siRNA therapies have recently been approved in the U and Europe for acute hepatic porphyria and hATTR amyloidosis, noted Meffen.
In terms of CMC considerations, most LNP formulations require parenteral or bolus intramuscular delivery. “The lipids that make up an LNP are more functional than a simple excipient, so need to be synthesized and controlled to a high grade and will need to be adequately described in regulatory filings,” explained Meffen. The likely need for frozen storage adds complexity on the distribution side, she added.
“Stepping back to the mRNA drug substance, manufacturing and testing are specialized, and scale-up can be challenging,” she said. Immunogenic response is possible with mRNA therapies for rare diseases, so manufacturers and regulatory professionals must be vigilant at all stages, since even small variations in manufacturing can have an impact on immunogenicity. Manufacturing siRNA products is a “very expensive” process that can take from 4 to 6 weeks. “Expertise in manufacturing and testing siRNA is essential, said Meffen. If the finished product is a liquid formulation, it will need careful handling during transportation to avoid causing changes in physical characteristics.
In addition to the usual drug quality attributes, mRNA drug substances have a unique set of attributes to consider, including mRNA integrity and concentration, residual DNA template and residual double-stranded DNA, said Meffen. Quality attributes specific to siRNA products include identification and purity control of both the sense-antisense duplex and the individual single strands.
RAPS: First published in Regulatory Focus™ by the Regulatory Affairs Professionals Society, the largest global organization of and for those involved with the regulation of healthcare products. Click here for more information.