Issued January 1, 2018
Issued
January 1, 2018
Application
Other • 761088
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
This is a Complete Response letter from the FDA to CELLTRION, Inc. regarding their Biologics License Application (BLA) 761088 for the proposed biosimilar product CT-P10. The FDA has determined that the application cannot be approved in its current form due to deficiencies identified in facility inspections, clinical data, product quality, and other regulatory aspects. The letter outlines specific issues and provides recommendations for addressing them prior to resubmission.
The application cannot be approved in its present form due to unresolved facility inspection findings, inadequate clinical data justification for biosimilarity, multiple deficiencies in manufacturing process control and product quality attribute characterization, and incomplete labeling information requiring updates upon resubmission.
During a recent inspection of the Celltrion, Inc. manufacturing facility, field investigator conveyed deficiencies. Satisfactory resolution of these deficiencies is required before BLA approval.
Recommended response: Address and resolve all deficiencies identified during the facility inspection.
Study CT-P10 3.3, in patients with advanced follicular lymphoma, was not adequately justified to detect differences between products, failing to support a demonstration of no clinically meaningful differences between CT-P10 and US-licensed Rituxan in terms of safety, purity, and potency. Observed differences in objective response rate (ORR) and adverse events require further justification.
Recommended response: Provide additional information and scientific justification to address the uncertainty raised by observed differences in Study CT-P10 3.3, particularly regarding ORR and adverse events, to support biosimilarity.
The characterization and assessment of the cell culture process were insufficient, leading to inadequate control over the process during manufacture. This impacts product quality and cell culture process consistency.
Recommended response: Improve characterization and assessment of the cell culture process to ensure adequate control and consistency during routine manufacture.
Proposed ranges for certain process parameters are unacceptable as their values exceed those evaluated during process validation, and adequate process characterization data supporting these limits were not provided.
Recommended response: Revise proposed acceptable ranges for commercial process to validation ranges or commercial manufacturing experience, or provide additional process characterization data to justify wider ranges.
Acceptable ranges for chromatography columns were based on insufficient data, not providing sufficient control for consistency during routine manufacture. Parameters should be justified using data from PPQ and commercial manufacturing runs.
Recommended response: Justify chromatography column parameter ranges with data from PPQ and commercial manufacturing runs, or provide data if wider ranges are desired.
Product fragments are identified as a critical quality attribute (CQA), but the impact of the process on fragment levels was not assessed during process development. It is unclear if proposed critical process parameters are sufficient to control fragment levels during routine manufacture.
Recommended response: Identify process unit operations that impact product fragment levels, and provide a complete summary and description of the control strategy for product fragments.
Deamidation at the heavy chain Asn55 (HC Asn55) site is identified as a CQA and controlled by a specific method, but data showing that changes in deamidation can be reliably detected by this method were not provided to support the proposed control strategy.
Recommended response: Provide data demonstrating the reliability of the method to detect changes in deamidation at HC Asn55 to support the control strategy.
Data provided show that increased afucosylated glycans (G0+G1) can affect FcγRIIIa binding and, consequently, ADCC activity of CT-P10. The proposed DS specification for glycans (G0 and Unidentified Peaks) does not provide adequate control of ADCC as it does not provide sufficient control of G1 content.
Recommended response: Propose DS specifications with acceptance criteria to control all main afucosylated glycans, provide assay validation data, and provide DS lot release and stability data to justify revised specifications.
Information regarding the stability testing plan and specifications for the CT-P10 master and working cell banks, provided in an IR response, was not updated in the relevant section of Module 3.
Recommended response: Update section 3.2.S.2.3.2 with the provided cell bank stability and specification information.
No data provided for FcγRIIIa binding affinity for drug product (DP) stored under long-term conditions (5±3°C) to support the current testing strategy, despite FcγRIIIa binding affinity being included in DS release and stability specifications.
Recommended response: Provide data for FcγRIIIa binding affinity during DP storage or include FcγRIIIa binding affinity testing in the DP stability program.
Data to support the adequacy of the proposed polysorbate 80 (PS80) lower limit were not provided.
Recommended response: Provide data to support the adequacy of the proposed PS80 lower limit.
A small portion of 100 mg CT-P10 DP vials from PPQ and commercial runs fail based on fill weight check and do not meet the requirement of extractable volume per USP<1>. Section 3.2.P.3.5 should be revised to reflect that these vials are quarantined and discarded.
Recommended response: Revise section 3.2.P.3.5 to reflect that vials failing fill weight checks and USP<1> requirements are quarantined and discarded.
Cited: USP<1>
The primary themes are insufficient clinical data to demonstrate biosimilarity, inadequate control strategies for critical manufacturing parameters and product quality attributes, and unresolved facility inspection findings, all of which prevent approval in the current form.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
Document viewer
Read the FDA letter and send context to the co-pilot at any time.