The U.S. Food and Drug Administration (FDA) issued two Complete Response Letters (CRLs) to South Korean manufacturer Celltrion. One was for a proposed biosimilar for Genentech and Biogen’s Rituxan for lymphomas and leukemias, and a proposed biosimilar to AbbVie’s Humira for rheumatoid arthritis, plaque psoriasis, Crohn’s disease and other autoimmune disorders.

Israel-based Teva Pharmaceutical Industries signed a deal in 2016 with Celltrion to commercialize the two biosimilars. The deal was for $160 million. They were submitted to the FDA in 2017, but have not been approved.

Celltrion spokesperson HeeWon Park, told Biopharma-Reporter, “The FDA Warning Letter issued to Celltrion on January 26, 2018 contributed in part to the receipt of the CRL. Celltrion is making progress addressing the concerns raised by the FDA in a Warning Letter issued in January and is committed to working with the agency to fully resolve all outstanding issues with the highest priority and urgency.”

Celltrion also indicates it expects to resubmit the applications fairly soon. “Then, we are expecting approvals in six months after resubmission according to regulatory timeline,” the company stated.

A Teva spokesperson told Biopharma-Reporter, that it will “continue to work closely with Celltrion with the goal of bringing the proposed trastuzumab and rituximab biosimilars to market in the U.S. Teva remains committed to gaining FDA approval and to bringing these products to market.”

These rejections are apparently based on an inspection of Celltrion’s facility in Incheon, South Korea by the FDA from May 22 to June 2, 2017. The FDA issued the Warning Letter on January 26, 2018. The letter summarized problems with the site’s current good manufacturing practice (CGMP) compliance.

The letter specifically cited “poor aseptic behavior,” “smoke study deficiencies,” “media fill deficiencies” and several other issues. The letter also stated, “Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer. Failure to correct these violations may also result in FDA refusing admission of articles manufactured at Celltrion, Inc., 23 Academy-ro, Yeonsu-gu, Incheon, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).”

This has potentially broader implications for Teva. The company’s fremanezumab, an anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibody whose active pharmaceutical ingredient (API) is manufactured at the same facility. The drug candidate was submitted to the FDA last year and has a decision date set for mid-June 2018.

The Center for Biosimilars notes, “U.S. regulatory rejection of the two products does not come entirely as a surprise; the Republic of Korea drug maker received the FDA’s Form 483 last year, noting 12 observations related to a range of issues, including incomplete records, inappropriately designed equipment, deficient environmental monitoring, and inadequate validation of sterilization processes. Then, in February 2018, Celltrion received a warning letter from the agency related to its manufacturing processes.”

CT-P10, the proposed rituximab biosimilar, was approved in Europe, where it is marketed under the names Blitzima, Ritemvia, Rituzena, and Truxima. And CT-P6, the Herceptin biosimilar, recently gained marketing authorization in Europe with Celltrion planning to launch it under the name Herzuma.