Approval Letter Other 761315 (Jan 1, 2025)

Significant fluctuations in NNC0172-2021 concentrations were noted, leading to potential subtherapeutic levels with missed doses. The application lacks a clear plan for dosing after missed doses and the proposed single PK monitoring after four weeks is deemed insufficient to ensure consistent therapeutic drug levels.

Recommended response: Provide a comprehensive plan for dosing after one or more missed doses, potentially including additional PK monitoring or repeat loading doses. Emphasize adherence to daily dosing and maintenance of therapeutic levels in a Medication Guide, labeling, and educational materials. Propose more frequent routine PK monitoring or provide further justification for the current plan.

The validation of the NNC0172-2021 ELISA is inadequate to support its use in testing clinical specimens. Specific issues include insufficient evaluation of native patient samples in correlation/cross-validation studies, lack of instrument-to-instrument and lot-to-lot precision assessment, identified interfering substances without dose-response studies, missing sample stability data, and absence of a root-cause analysis for underestimation of concentrations in contrived samples.

Recommended response: Conduct comprehensive validation studies for the NNC0172-2021 ELISA, including evaluation of sufficient native patient samples across relevant concentration ranges, assessment of instrument and lot precision, dose-response studies for interfering substances, provide sample stability data, and perform a root-cause analysis for observed underestimation.

The information and data provided are not sufficient to address the risk of an unspecified impurity (redacted as (b)(4)) on safety and efficacy, and the control strategy for this impurity is inadequate to ensure product quality, safety, and efficacy.

Recommended response: Provide sufficient information and data to address the risk of the impurity on safety and efficacy, and implement an adequate control strategy to ensure product quality, safety, and efficacy.

Some of the proposed DS release and stability specifications acceptance criteria are inadequate to ensure batch-to-batch consistency at release and on stability.

Recommended response: Revise and justify the drug substance release and stability specifications to ensure batch-to-batch consistency.

Some of the proposed DP release and stability (shelf-life) specifications acceptance criteria are inadequate to ensure batch-to-batch consistency at release and on stability.

Recommended response: Revise and justify the drug product release and stability specifications to ensure batch-to-batch consistency.

The revised MCB and WCB stability protocols are inadequate to ensure consistent cell bank performance and to determine if a new cell bank should be manufactured in a timely manner, potentially leading to manufacturing disruptions and drug shortages.

Recommended response: Revise the MCB and WCB stability protocols to include well-defined tests and acceptance criteria to ensure consistent cell bank performance.

The protocols for PRM and SRM stability are inadequate to ensure consistent control over the stability of these reference materials.

Recommended response: Revise the PRM and SRM stability protocols to ensure consistent control over the stability of the current reference materials.

The DS post-approval stability protocol is inadequate to ensure DS stability to the end of shelf-life post approval.

Recommended response: Revise the DS post-approval stability protocol to ensure drug substance stability to the end of shelf-life post approval.

The DP post-approval stability protocol is inadequate to ensure DP stability to the end of shelf-life post approval.

Recommended response: Revise the DP post-approval stability protocol to ensure drug product stability to the end of shelf-life post approval.

Insufficient information was provided on how the tracking of cartridge and pen-injector batches using LIMS links to the identity testing conducted as part of release specifications, failing to comply with 21 CFR 610.14.

Recommended response: Revise section 3.2.P.3.3 to specify the physical characteristics used during tracking (e.g., cap color or markings) to ensure correct identity after all labeling operations, in compliance with 21 CFR 610.14.

Cited: 21 CFR 610.14

The EPRs (dose accuracy, activation force, hold force, and injection time) of device constituents of the combination product were not included in the DP post-approval stability protocol, despite previous requests, which is necessary to monitor batch-to-batch consistency post-approval.

Recommended response: Add the EPRs (dose accuracy, activation force, hold force, and injection time) to the DP post-approval stability protocol.

The EPRs (activation force, hold force, and injection time) of device constituents of the combination product were not included in the DP release specifications, despite previous requests, to align with the DP post-approval stability protocol.

Recommended response: Add the EPRs (activation force, hold force, and injection time) to the DP release specifications.