US FDA•United StatesAL•Approval Letter

Approval Letter Other 761082 (Jan 1, 2022)

Issued January 1, 2022

Issued

January 1, 2022

Application

Other • 761082

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due January 1, 2023Product may be marketed.

Summary

The FDA issued a Complete Response Letter for Biologics License Application (BLA) 761082 for Theragrastim, indicating that the application cannot be approved in its current form due to several deficiencies, including the need for a facility inspection, issues with stability protocols and analytical methods, and requirements for labeling and safety updates.

Key points

An inspection of the Kashiv Biosciences LLC DS manufacture facility (FEI 3011289655) is required and must be conducted and findings assessed.
Update the stability protocols for the in-house primary and working reference standards to provide adequate trending analysis strategies for EC50 values.
Evaluate whether there is an EC50 value drift based on absolute values generated in the potency assay.
Provide an updated qualification report for the adequately qualified in-house Working Reference Standard (WRS).
Use an adequately qualified WRS as the standard in stability testing for the Primary Reference Standard (PRS).
Establish a stability acceptance criterion for the EC50 for the WRS based on a trend analysis of EC50 values obtained during routine release and stability testing.
Provide adequate information to support the proposed change to the potency method (STM-0118) to ensure no impact on method validation and test article data.
Submit draft carton and container labeling.

Cited reasons

Uncompleted Facility Inspection for DS Manufacture Facility
Inadequate Stability Protocols for In-house Primary and Working Reference Standards
Insufficient Data for Potency Assay Method Change
Reserved Comment on Proposed Prescribing Information
Missing Draft Carton and Container Labeling
Resubmit Proposed Proprietary Name
Comprehensive Safety Update Required
Lack of Stability Data for Deliverable Volume

Recommended actions

An inspection of the Kashiv Biosciences LLC DS manufacture facility (FEI 3011289655) is required and must be conducted and findings assessed.
Update the stability protocols for the in-house primary and working reference standards to provide adequate trending analysis strategies for EC50 values.
Evaluate whether there is an EC50 value drift based on absolute values generated in the potency assay.
Provide an updated qualification report for the adequately qualified in-house Working Reference Standard (WRS).
Use an adequately qualified WRS as the standard in stability testing for the Primary Reference Standard (PRS).
Establish a stability acceptance criterion for the EC50 for the WRS based on a trend analysis of EC50 values obtained during routine release and stability testing.
Provide adequate information to support the proposed change to the potency method (STM-0118) to ensure no impact on method validation and test article data.
Submit draft carton and container labeling.

Deficiency summary

The application cannot be approved in its present form due to an uncompleted manufacturing facility inspection, inadequate stability protocols for reference standards, insufficient data to justify potency assay changes, and pending labeling and safety update requirements. These issues collectively prevent a full assessment of product quality, safety, and manufacturing compliance.

Findings

Uncompleted Facility Inspection for DS Manufacture Facility

Severity: critical

An inspection of the Kashiv Biosciences LLC DS manufacture facility (FEI 3011289655) is required to assess its ability to conduct manufacturing operations in compliance with CGMP. The inspection could not be conducted due to travel restrictions, preventing approval until completed and findings assessed.

Recommended response: Coordinate with FDA to schedule the required facility inspection and ensure all manufacturing operations comply with CGMP.

Cited: Compliance with Current Good Manufacturing Practices

Inadequate Stability Protocols for In-house Primary and Working Reference Standards

Severity: major

The current in-house reference standard has not been qualified appropriately due to Out-of-Specification (OOS) results. Stability protocols need updating to include adequate trending analysis strategies for EC50 values and an updated qualification report for the working reference standard (WRS). A stability acceptance criterion for WRS EC50 based on trend analysis is also required.

Recommended response: Update stability protocols for primary and working reference standards to include trending analysis for EC50 values, provide an updated WRS qualification report, and establish EC50 stability acceptance criteria for WRS.

Cited: General BLA requirements for product quality and stability

Insufficient Data for Potency Assay Method Change

Severity: major

The summary information provided to justify changes made to the potency assay (STM-0118, change control CC-20-036) was inadequate, lacking supporting data to assess the appropriateness of the proposed change and its impact on method validation and test article data.

Recommended response: Provide comprehensive data and information to support the proposed change to the potency assay method, demonstrating no impact on method validation and test article data.

Cited: General BLA requirements for analytical method validation

Reserved Comment on Proposed Prescribing Information

Severity: minor

FDA reserves comment on the proposed labeling until the application is otherwise adequate. The sponsor is encouraged to review labeling review resources, regulations, and guidance documents, including those for biosimilar products.

Recommended response: Review and revise proposed prescribing information according to FDA labeling resources and biosimilar guidance, preparing for submission once other deficiencies are addressed.

Cited: General requirements for prescribing information

Missing Draft Carton and Container Labeling

Severity: minor

Draft carton and container labeling needs to be submitted.

Recommended response: Submit draft carton and container labeling.

Cited: General requirements for carton and container labeling

Resubmit Proposed Proprietary Name

Severity: minor

The proposed proprietary name, Releuko, was conditionally accepted pending approval. It needs to be resubmitted when responding to application deficiencies.

Recommended response: Resubmit the proposed proprietary name, Releuko, with the complete response to deficiencies.

Cited: FDA proprietary name review process

Comprehensive Safety Update Required

Severity: major

A comprehensive safety update is required with the response to deficiencies. This includes detailed changes/findings in the safety profile, new clinical study data, tabulations of combined safety data, comparison of adverse event frequencies, retabulation of premature study discontinuations, case reports for deaths/serious AEs, information on common AEs, updated exposure information, worldwide safety experience, and English translations of foreign labeling.

Recommended response: Prepare and submit a comprehensive safety update incorporating all new nonclinical and clinical data, worldwide experience, and updated labeling translations as specified.

Cited: General BLA requirements for safety data updates

Lack of Stability Data for Deliverable Volume

Severity: major

Stability data for deliverable volume to support the proposed 24-month shelf life for the drug product has not been provided, despite previous recommendations to include expellable volume testing at the end of the proposed shelf life.

Recommended response: Provide stability data for deliverable volume, including expellable volume testing at the end of the proposed shelf life, to support the 24-month shelf life claim.

Cited: General BLA requirements for product quality and performance

Regulatory context

Submission stage: final decision
Regulatory pathway: 351(k) Biosimilar BLA

Impact

Impact score: 0.95
Estimated delay: 365 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

The application faces significant hurdles primarily related to manufacturing facility compliance, comprehensive CMC data for product quality and stability, and complete safety data updates. These core issues prevent approval, necessitating a thorough resubmission addressing all identified deficiencies.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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