“2.2.3. Finished Medicinal Product
SM-102
CQAs [critical quality attributes], CPPs [control process parameters] and critical attributes of the materials used for the manufacture of SM-102 are missing. The applicant will provide those post-marketing.
Control of PEG2000-DMG
... The specification is currently not acceptable. Polydispersity should be included in the specification for PEG2000-DMG post-approval. Numerical limits for specified and unspecified impurities will be included in the PEG2000-DMG specification post-approval. The current reporting of impurities is not acceptable. Characterisation data for impurities which are reported under ‘content of unknown’ should be provided post-approval.
2.3.3. Pharmacokinetics
... [T]he biodistribution of the vaccine platform was evaluated with mRNA-1647 in a non-GLP, single-dose, intramuscular injection study in Sprague Dawley rats. The objectives of this study were to determine the tissue distribution and pharmacokinetic characteristics of mRNA-1647 constructs following IM [intramuscular] administration...
Concentrations of mRNA-1647 were quantifiable in the majority of tissues examined at the first time point collected (2 hours post-dose) and peak concentrations were reached between 2- and 24-hours
post-dose in tissues with exposures above that of plasma. Besides injection site [muscle] and lymph nodes [proximal and distal], increased mRNA concentrations (compared to plasma levels) were found
in the spleen and eye... Low levels of mRNA could be detected in all examined tissues except the kidney. This included heart, lung, testis and also brain tissues, indicating that the
mRNA/LNP platform crossed the blood/brain barrier, although to very low levels (2-4% of the plasma level). Liver distribution of mRNA-1647 is also evident in this study, consistent with the literature
reports that liver is a common target organ of LNPs...
2.3.4 Toxicology ...
Reproduction Toxicity
A GLP-compliant reproductive and developmental toxicology (DART) study with mRNA-1273 has been conducted in female Sprague Dawley CD rats.
IM [intramuscular] administrations of mRNA-1273 to female SD 1 rats at the human clinical dose, twice before mating and twice during gestation, was associated with non-adverse effects including thin fur cover, swollen hindlimbs and limited usage of the hindlimb. However, there were no mRNA-1273-related effects on female fertility, embryo-foetal or post-natal survival, growth or development in the F1 offspring. The mRNA-1273-related non-adverse effects were limited to an increase in the number of foetuses with common skeletal variations of 1 or more rib nodules and 1 or more wavy ribs, with no effect on the viability and growth on the F1 generation pups.
In this study, no vaccine dose was administered during the early organogenesis, to address the direct embryotoxic effect of the components of the vaccine formulation. However, such a risk is considered low in humans, given the non-live organism nature of mRNA-1273 and the low risk of genotoxic effect of SM-102-containing LNP in humans. The overall pregnancy index was numerically lower in mRNA-1273 vaccinated female rats (84.1%), compared to control animals (93.2%), but remains within the Test Facility’s historical control range (low range being 75%).”
© European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged.