Approval Letter Other 761085 (Jan 1, 2019)

Unsolicited information and changes were submitted during the BLA review cycle, including process validation data from new drug product (DP) lots and changes to the DP post-approval stability protocol. The extent of these changes has not been fully determined, impacting the assessment of approvability. A comprehensive list of all unsolicited information and changes added to the BLA after the initial receipt on May 15, 2017, is required.

Recommended response: Provide a comprehensive list of all unsolicited changes and their rationale. Ensure all future submissions adhere to established amendment procedures and clearly document all modifications.

Routine bioburden monitoring was not performed to verify continued microbial control of the drug product. Implementation of routine bioburden monitoring is required, along with a description of the test method, method qualification, summary data, and the qualification report.

Recommended response: Implement a robust routine bioburden monitoring program for the drug product. Provide a detailed description of the test method, full method qualification, summary data, and the qualification report.

The drug substance (DS) reference material management program does not generate sufficient quantities of a given reference material lot to support all required testing. Procedures need revision to ensure adequate quantities for all necessary testing, including qualification of future reference materials. Additionally, the DS reference material qualification and requalification protocol must include adequate stability monitoring of the reference materials.

Recommended response: Revise reference material qualification procedures to ensure sufficient quantities are generated for all required testing. Update qualification and requalification protocols to include adequate stability monitoring of reference materials.

The applicant removed testing points (3, 6, 9, and 18 months) from the post-approval stability protocol without providing sufficient stability data to support such a reduced program. The updated annual post-approval stability protocol is inadequate to ensure that potential changes to commercial DP during storage are detected in a timely manner. Revision to include these testing points, as recommended by ICH Q5C guidelines, is required.

Recommended response: Revert to a comprehensive stability testing protocol including all standard time points (3, 6, 9, 18 months) or provide robust data to justify any reduction, aligning with ICH Q5C guidelines.

The applicant's response indicated that a 'soon to be established distributor' would be responsible for certain release operations (visual inspection, verification of COAs, quantity, temperature maintenance) and that the applicant would rely on the distributor’s SOPs and QA. The agency states that if the distributor performs release operations, they fit the definition of a manufacturer per 21 CFR 600.3 (t), (u), and (aa) and should be listed as such in the license application.

Recommended response: Clarify the roles and responsibilities of the distributor. If the distributor performs manufacturing functions, ensure they are properly listed as a manufacturer in the BLA and comply with all associated regulatory requirements.

Cited: 21 CFR 600.3 (t), 21 CFR 600.3 (u), 21 CFR 600.3 (aa)

The agency reserves comment on the proposed labeling until the application is otherwise adequate. The applicant is encouraged to review PLR Requirements, Pregnancy and Lactation Labeling Final Rule, and the SRPI checklist. An updated content of labeling in Structured Product Labeling (SPL) format, as per 21 CFR 601.14(b), is required.

Recommended response: Revise labeling to comply with PLR requirements, Pregnancy and Lactation Labeling Final Rule, and SRPI checklist. Submit updated content in SPL format.

Cited: 21 CFR 601.14(b)

The proposed proprietary name, Jeuveau, was found acceptable pending approval of the application in the current review cycle. The applicant must resubmit the proposed proprietary name when responding to the application deficiencies.

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

A comprehensive safety update is required, including data from all nonclinical and clinical studies/trials, detailed description of significant changes, retabulation of adverse events (new data combined with original, comparison tables), reasons for premature discontinuation, case report forms/narratives for deaths/serious AEs, changes in common AEs, updated exposure information, worldwide safety experience, and English translations of foreign labeling.

Recommended response: Conduct a thorough safety update as specified, providing all requested data, analyses, and documentation from all relevant studies and worldwide experience.