Celltrion acknowledges CRLs in potential hurdle for Teva
- Celltrion Inc. on April 6 acknowledged receipt of complete response letters (CRL) from the Food and Drug Administration for the Korean company's Biologics License Applications for proposed biosimilars to cancer drugs Rituxan and Herceptin.
- Celltrion is partnered with Teva Pharmaceutical Industries Ltd. on both biosimilar candidates and manufactures the drugs at a facility in South Korea, which was recently cited by the FDA for GMP-related issues.
- Receipt of the CRLs for the two biosimilar candidates could also spell trouble for Teva's BLA for fremanezumab, an experimental treatment for migraine prevention.
Celltrion sought to put the best face on the development, but a CRL is never good news.
"Celltrion is confident that the issues raised by the FDA will be resolved in a timely manner," noted a company release. "We can confirm that the resubmission will be in place relatively soon. Then, we are expecting approvals in 6 months after resubmission according to regulatory timeline."
The CRLs were "directly related" to a prior FDA warning letter issued to Celltrion in January, according to the company. This could put investigational candidates being made at the Celltrion plant in jeopardy — including Teva's migraine prevention hopeful fremanezumab, a CGRP inhibitor.
Right now, fremanezumab has a regulatory action date of June 16, but the announcement of the CRLs on the two biosimilars hints at the FDA's view of drug product manufacturing at the Celltrion site.
In a fourth-quarter earnings call earlier this year, Teva said the problems at Celltrion could delay approval of fremanezumab, which would hand an advantage to rival migraine drugmakers.
"We are in active dialogue with FDA in order to ensure that this warning letter would not affect the supplies of API from Celltrion to our fremanezumab program," said Teva CEO Kåre Schultz at the time. "We are optimistic that we would be able to prove that the API manufacturing is in good shape, but it, of course, remains to be settled in a discussion with FDA."
Many of the manufacturing problems at the Incheon, South Korea site were due to problems with aseptic procedures.
Fill-finish outsourcing continues to top the list of bioprocessing operations being outsourced, according to Eric Langer of BioPlan Associates. Advances in automation and barrier isolators are considered good ways to keep drugs sterile during manufacturing, even though some form of manual operation will likely be necessary for biologics.
To further compound the issue, Celltrion is the sole-source provider of active pharmaceutical ingredient for fremanezumab and for two biosimilar candidates Teva and Celltrion are developing together. Sole sourcing is a risky practice. While this risk could be reduced by qualifying a secondary source for API — which Teva said it plans to do — time is running out to backstop production of fremanezumab API with another producer before the FDA decides on approval.
More than 75% of FDA recalls between 2004 and 2011 involved sterile products, and approximately 80% of these recalls were linked to lack of sterility assurance. Rather than having to issue recalls as a result of microbial contamination, issuing CRLs from the start to spur manufacturers to improve their facilities may be an easier approach.