Approval Letter Other 761066 (Jan 1, 2019)

Summary

This document is a Complete Response letter from the FDA to Samsung Bioepis Co., Ltd. regarding their Biologics License Application (BLA) 761066 for SB4. The FDA has determined that the application cannot be approved in its present form due to various deficiencies related to product quality, prescribing information, proprietary name, and safety updates.

Key points

• Generate an appropriately qualified primary reference standard (PRS) and provide data to link it to clinical study materials and analytical similarity assessment.
• Clearly define actions to be taken when samples are outside rejection/action limits, including segregation of affected lot portions.
• Provide shipping validation data for the drug product from real-time studies or sufficiently representative simulated studies, including assessment of product quality pre- and post-shipping.
• Update the drug product manufacturing process in Section 3.2.P.3.3 to ensure samples for identity testing are taken after labeling operations, complying with 21 CFR 610.14.
• Provide sterilization validation for the minimum hold time for items used to manufacture SB4.
• Include sterile filtration hold time as a critical process parameter and provide respective acceptance criteria in section 3.2.P.3.4.
• Review and revise proposed labeling to conform with format items in regulations and guidances, using the SRPI checklist.
• Include updated content of labeling in Structured Product Labeling (SPL) format.

Cited reasons

• Primary Reference Standard (PRS) and Working Reference Standard (WRS) not appropriately qualified
• Insufficient assurance of drug product quality during commercial shipping and distribution
• Drug product manufacturing process needs update for identity testing sample point
• Deficient sterilization validation for product-contact equipment
• Sterile filtration parameter not included as a critical process parameter
• Comments on proposed labeling reserved
• Resubmit proposed proprietary name
• Provide a comprehensive safety update

Recommended actions

• Generate an appropriately qualified primary reference standard (PRS) and provide data to link it to clinical study materials and analytical similarity assessment.
• Clearly define actions to be taken when samples are outside rejection/action limits, including segregation of affected lot portions.
• Provide shipping validation data for the drug product from real-time studies or sufficiently representative simulated studies, including assessment of product quality pre- and post-shipping.
• Update the drug product manufacturing process in Section 3.2.P.3.3 to ensure samples for identity testing are taken after labeling operations, complying with 21 CFR 610.14.
• Provide sterilization validation for the minimum hold time for items used to manufacture SB4.
• Include sterile filtration hold time as a critical process parameter and provide respective acceptance criteria in section 3.2.P.3.4.
• Review and revise proposed labeling to conform with format items in regulations and guidances, using the SRPI checklist.
• Include updated content of labeling in Structured Product Labeling (SPL) format.

Deficiency summary

The application cannot be approved in its present form due to significant product quality deficiencies, including inadequate qualification of primary and working reference standards, insufficient validation of commercial drug product shipping, and issues with manufacturing process controls such as identity testing sample points, sterilization validation, and sterile filtration parameters. Additionally, a comprehensive safety update is required, and labeling comments are reserved pending resolution of other issues.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

351(k) BLA

Impact

Impact score

0.95

Estimated delay

545 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The application faces critical product quality and manufacturing control issues, particularly concerning the foundational aspects of reference standard qualification and validation of commercial processes. These deficiencies indicate a need for robust data and controls to ensure product quality, consistency, and sterility assurance, impacting the overall approvability of the biosimilar.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%