About a month before Pfizer and BioNTech won an emergency approval for their COVID-19 vaccine in Europe, regulators raised flags about lower than expected levels of intact mRNA in commercial batches, reports the BMJ.
The European Medicines Agency described “a significant difference” in RNA in clinical batches and proposed commercial batches, according to information leaked from an EMA cyber attack in December, which the BMJ subsequently revised.
Although the production problem has been resolved – and the Pfizer vaccine has already been approved in Europe – the leaks show the “complexities of quality assurance” for mRNA vaccines, especially with regard to RNA instability, said the BMJ. It is a problem that affects all mRNA developers, including Moderna and CureVac. This instability is the reason for the vaccine’s cold chain requirements and the need to encapsulate the mRNA in lipid nanoparticles, BMJ said.
The question comes down to whether the commercial manufacture of Pfizer and BioNTech was up to the task. EMA scientists had doubts about “truncated and modified mRNA species present in the finished product” and, as a result, filed two main objections with Pfizer and raised a number 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”.
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Having a complete and intact mRNA molecule is essential for the performance of an mRNA vaccine, and “[even] a minor degradation reaction, anywhere along an mRNA strand, can severely slow down or disrupt the proper translation performance of that strand and thus result in incomplete expression of the target antigen, “wrote Daan JA Crommelin, professor of biopharmaceuticals , and colleagues at The Journal of Pharmaceutical Sciences last year, as quoted by BMJ.
For the Pfizer product, the mRNA integrity for clinical batches was around 78%, compared with 55% for the proposed commercial batches, states an email from the EMA dated 23 November. This difference has raised concerns that Pfizer and regulators have addressed.
The effectiveness of the vaccine depends on the presence of adequate levels of intact mRNA, according to the EMA. Regulators and Pfizer have not said that the level of mRNA integrity is acceptable.
“It is important to note that each batch of vaccines is tested by the official drug control laboratory (OMCL) – the Paul-Ehrlich Institute in Germany – prior to the launch of the final product,” said Pfizer in its e-mailed statement.
“As a result, the quality of all vaccine doses that are placed on the market in Europe has been tested twice to ensure compliance with the specifications agreed with the regulatory authorities. If a batch does not meet these required specifications, the product will not be released for use in Europe. “
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In another leaked email dated November 25, an undisclosed source in the United States said that “the last batches indicate that% of intact RNA is around 70-75%, which makes us cautiously optimistic that additional data can solve the problem “.
Meanwhile, Pfizer told Fierce Pharma that its EMA authorization indicates “that all issues raised during the procedure have been addressed in a satisfactory manner and the effectiveness, safety and quality of the vaccine could be demonstrated in the data presented.” Regulators in Canada, the United States and many other countries have also authorized the shot.