About a month before Pfizer and BioNTech won an emergency nod for their COVID-19 vaccine in Europe, regulators raised flags about lower-than-expected levels of intact mRNA in commercial batches, the BMJ reports.
The European Medicines Agency outlined “a significant difference" in the RNA in clinical batches and the proposed commercial batches, according to information leaked from an EMA cyberattack in December, which the BMJ subsequently reviewed.
While the production issue has since been resolved—and Pfizer's vaccine has since won approval in Europe—the leaks show the “complexities of quality assurance” for mRNA vaccines, especially with regards to RNA instability, the BMJ said. It’s an issue that affects all mRNA developers, including Moderna and CureVac. That instability is the reason for the shots’ frigid cold chain requirements and the need to encapsulate mRNA in lipid nanoparticles, BMJ said.
The issue boils down to whether Pfizer and BioNTech's commercial manufacturing was up to par. EMA scientists had misgivings about “truncated and modified mRNA species present in the finished product," and as a result, filed two major objections with Pfizer and raised a slew of additional questions, the report says.
In an email to Fierce Pharma, Pfizer noted that discussions with regulators about vaccine quality are a "normal component of the regulatory review process."
Having a complete, intact mRNA molecule is essential to the performance of an mRNA vaccine, and “[even] a minor degradation reaction, anywhere along a mRNA strand, can severely slow or stop proper translation performance of that strand and thus result in the incomplete expression of the target antigen," Daan J.A. Crommelin, professor of biopharmaceutics, and colleagues wrote in The Journal of Pharmaceutical Sciences last year, as quoted by BMJ.
For the Pfizer product, mRNA integrity for clinical batches came in at about 78%, compared with 55% for the proposed commercial batches, an EMA email dated November 23 states. That difference led to the concerns that Pfizer and the regulators worked through.
Vaccine efficacy does depend on the presence of appropriate levels of intact mRNA, according to the EMA. The regulators and Pfizer haven't said what level of mRNA integrity is acceptable.
"It’s important to note that each batch of vaccines is tested by the official medicinal control laboratory (OMCL)—the Paul-Ehrlich Institute in Germany—before final product release," Pfizer said in its emailed statement.
"As a result, the quality of all vaccine doses that are placed on the market in Europe has been double tested to ensure compliance with the specifications agreed upon with the regulatory authorities. Should a batch not meet these required specifications, the product wouldn’t be released for use in Europe."
In another leaked email dated November 25, an undisclosed source from the U.S. said that the "latest lots indicate that % intact RNA are back at around 70-75%, which leaves us cautiously optimistic that additional data could address the issue.”
Meanwhile, Pfizer told Fierce Pharma its EMA authorization indicates "that all the questions raised during the procedure were addressed satisfactorily and the efficacy, safety and quality of the vaccine could be demonstrated on the data submitted." Regulators in Canada, the U.S. and many other countries have also authorized the shot.