About a month before Pfizer and BioNTech won an emergency nod for their COVID-19 vaccine in Europe, regulators hoisted flags over lower-than-expected levels of intact mRNA in commercial groups, the BMJ reported.
The European Medicines Agency has identified a “significant difference” in the RNA in clinical groups and the proposed commercial groups, according to information leaked from an EMA cyber attack in December, which the BMJ subsequently reviewed.
While the manufacturing issue has since been resolved – and Pfizer’s vaccine has since been approved in Europe – the leaks show the “complexity of quality assurance” for mRNA vaccines, particularly with regard to RNA instability, the BMJ said. This is an issue that affects all mRNA developers, including Moderna and CureVac. The instability is the reason for the icy cold chain requirements of the shots and the need to encapsulate mRNA in lipid nanoparticles, BMJ said.
The issue is that Pfizer and BioNTech’s commercial manufacturing was up to par. EMA scientists were skeptical about ‘truncated and modified mRNA species found in the final product’, and as a result submitted two major objections to Pfizer, raising a slew of additional questions, the report said.
In an email to Fierce Pharma, Pfizer notes that discussions with regulators about the quality of the vaccine are a ‘normal part of the review process.’
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Having a complete, intact mRNA molecule is essential for the execution of an mRNA vaccine, and ‘[even] a slight degradation reaction, anywhere along an mRNA strand, can severely slow or stop the proper translation performance of the strand and thus result in the incomplete expression of the target antigen, ‘writes Daan JA Crommelin, professor of biopharmaceuticals, and colleagues in The Journal of Pharmaceutical Sciences last year, as quoted by BMJ.
For the Pfizer product, mRNA integrity for clinical groups is approximately 78%, compared to 55% for the proposed commercial groups, according to an EMA email of 23 November. This difference has led to concerns raised by Pfizer and regulators.
However, according to the EMA, vaccine efficacy depends on the presence of appropriate levels of intact mRNA. The regulators and Pfizer did not say what level of mRNA integrity is acceptable.
“It is important to note that each group of vaccines is tested by the official Medical Control Laboratory (OMCL) – the Paul-Ehrlich Institute in Germany – before the final product is released,” Pfizer said in an email. .
“As a result, the quality of all doses of vaccines placed on the market in Europe has been doubly tested to ensure compliance with the specifications agreed with the regulatory authorities. If a group does not meet the required specifications the product would not be released for use in Europe. ‘
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In another email leaked on November 25, an unknown source from the US said that the “latest lots indicate that% intact RNA is around 70-75%, which leaves us cautiously optimistic that additional data can handle problem. “
Meanwhile, Pfizer told Fierce Pharma that the EMA authorization indicates that all the questions raised during the procedure have been satisfactorily addressed and that the efficacy, safety and quality of the vaccine can be proven on the basis of the data. Regulators in Canada, the US and many other countries have also approved the shot.