Prestige BioPharma’s recent failure to get European approval for its Herceptin biosimilar could have resulted from the company’s changes in the manufacturing of the biosimilar during a phase-3 trial, the company said.

The manufacturing change was due to the “product drift” of the original drug Herceptin. The company will strongly appeal this to the European Medicines Agency (EMA).

Product drift refers to a change in the product over time due to manufacturing changes.

On Friday, Prestige BioPharma said it received a negative opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP). This meant that the company could not obtain marketing approval for its biosimilar in Europe.

Later on Friday, the company filed a second disclosure, explaining more details of what happened.

“The CHMP seemed to notice a difference between the manufacturing process of the clinical batch of HD201 and that of the commercial batch,” Prestige BioPharma said. “It expressed a negative opinion because there was insufficient evidence that the commercial batch HD201 of was the biosimilar referencing the original drug,”

Responding to Korea Biomedical Review’s inquiry, Prestige BioPharma admitted that the company changed the manufacturing process of HD201 twice during a phase 3 study of the biosimilar.

“Once, we did it to keep up with the product drift of the original drug Herceptin, and another time, for upscaling the manufacturing for commercial use,” an official at Prestige BioPharma said.

The official named the batch produced for the clinical trial A, the next batch with a manufacturing change B, and the final batch for commercialization C.

“All the A, B, and C batches were used for the phase 3 clinical trial,” he said.

“Our company, as a biosimilar maker, changed the manufacturing process to keep up with the change in the original drug’s quality. So, we thought the EMA would compare A plus B with C.”

However, the EMA excluded A and compared only B with C. This must have led the EMA to think that the manufacturing process of HD201 for the clinical trial and that for commercial use was different.

“The clinical trial indeed took a relatively long time, but the EMA’s decision was unscientific,” he said.

Samsung Bioepis has emphasized product drift in Herceptin to argue that its biosimilar had better quality than the reference drug.

At the Korean College of Rheumatology’s annual meeting over the weekend, Herceptin’s product drift in 2019 was mentioned.

However, whether the EMA would recognize Prestige BioPharma’s appeal and whether the company can prove Herceptin’s product drift is unclear.

The company said Prestige BioPharma had a similar experience where it failed to prove the biosimilar’s bioequivalence due to Herceptin’s product drift in a phase 3 trial. Later, the drift was recognized as justifiable, and the biosimilar eventually obtained the license. However, the company refused to mention in which country the case occurred.

The company mentioned other cases such as Puma Biotechnology’s Nerlynx (neratinib maleate), Takeda’s Ninlaro (ixazomib citrate), and Proveca’s Sialanar (glycopyrronium bromide) that initially received a negative opinion from the EMA but reversed the decision later.

Prestige BioPharma can apply for re-examination to the EMA within 60 days after the first opinion, and it can receive the result within 60 days from the date of application.