Approval Letter Other (Nov 13, 2025)

The NDA has not provided adequate characterization of the aerosol, including aerosol composition, batch formula, batch data, stability data, identity, strength, purity, delivered dose, generator yield, generator duty cycle and generator recertification period. Critical quality attributes and specifications have not been established to ensure identity, strength, quality, purity, or potency.

Recommended response: Develop a comprehensive quality program to characterize and control the Technegas aerosol drug product. Validate aerosol production methods, propose and describe suitable analytical methods with validation, and establish justified specifications for critical product quality attributes. Submit results from at least three production runs at minimum and maximum radioactivity loads.

Cited: 21 CFR 314.50(d) (ii)((a))

Aerosol batch data from validated analytical methods for at least three registration batches are required to support commercial aerosol drug production and in-process controls. Batches must meet specifications and be produced according to the proposed regulatory commercial production process using sodium pertechnetate injection solution from approved manufacturers.

Recommended response: Provide aerosol batch data from validated analytical methods for at least three registration batches, ensuring they meet specifications and are produced under commercial conditions using sodium pertechnetate from approved US manufacturers. Revise the regulatory production description as previously advised.

Validated analytical methods suitable for characterizing the aerosol drug particle size distribution, radioactivity, and aerosol yield need to be developed. Standard methods may not be suitable due to short expiry and radioactivity.

Recommended response: Develop and validate new analytical methods for aerosol characterization, potentially collaborating with radiopharmaceutical drug development experts. Submit detailed method descriptions and validation data for each method.

Inadequate specifications for the crucible (on release or stability) have been provided. Batch data, stability data, and a post-approval stability protocol for the crucibles are missing.

Recommended response: Develop a quality program to characterize and control the crucible. Revise crucible specifications, submit release and stability data that meet specifications, and provide a stability protocol for the crucible.

The current environmental controls within the crucible manufacturing suite are inadequate to assure crucible product quality.

Recommended response: Establish and monitor minimum environmental controls in the crucible manufacturing suite prior to packaging to meet the requirements of 21 CFR Part 211.46.

Cited: 21 CFR Part 211.46

The NDA has not established adequate controls at each stage of the crucible manufacturing process related to validated operating parameters, in-process controls to support critical quality attributes. Gaps exist in raw data generation, storage, and documentation.

Recommended response: Implement a robust manufacturing control strategy for the crucible, addressing validated operating parameters, in-process controls, raw data generation, storage, and documentation.

Adverse test observations noted for the crucible shipping studies have not been addressed. Corrective actions or proposed design changes for primary or secondary packaging are lacking.

Recommended response: Provide updated test reports, address all adverse test observations, detail corrective actions, and propose any necessary packaging design changes for primary and secondary packaging. Any packaging change will require a new shipping study.

Failure to demonstrate consistent and reliable production of the Tc-99m carbon aerosol under good manufacturing conditions and documented registration batches to comply with actual yield and % of theoretical yield requirements. Issues also exist regarding 21 CFR Part 4 and 21 CFR Part 820 if adopting a streamlined approach.

Recommended response: Demonstrate consistent and reliable production of the Tc-99m carbon aerosol under good manufacturing conditions, ensuring compliance with yield requirements and relevant regulations (21 CFR Part 211.103, 21 CFR Part 4, 21 CFR Part 820).

Cited: 21 CFR Part 211.103, 21 CFR Part 4, 21 CFR Part 820

The reliability assessment report for the TechnegasTM system is unacceptable as it is not based on an approved protocol/verification test but exclusively on customer complaints data.

Recommended response: Submit a proper verification protocol, analytical tests/methods, specifications, acceptance criteria, and a final report for the reliability assessment of the TechnegasTM system.

Proposed procedures for annual recertification do not address ongoing yield monitoring of the final drug product by the TechnegasTM system as approved in drug specification.

Recommended response: Revise the proposed procedures to include ongoing yield monitoring of the final drug product by the TechnegasTM system, aligning with approved drug specifications.

Details on the calculations performed in determining exposure doses and threshold values used in calculating margin of safety values for all detected chemicals are missing.

Recommended response: Provide detailed, tabulated information on exposure dose calculations, including justification for selected values, exposure metrics, conversion factors, toxicity thresholds, and uncertainty factors.

Raw data from the CYC-009 study indicate a high rate of operator intervention for dyspnea/hypoxia. The NDA lacks a clear upper time limit for Technegas administration, instructions for operators on providing room air/supplemental oxygen, and breathing instructions for optimal risk mitigation.

Recommended response: Provide a detailed analysis of patient breathing methods from the CYC-009 study, clarifying relationships to other investigations and discussing advantages/disadvantages for biodistribution and risk mitigation. Add the missing information to instructions for prescribers and device operators, and re-prioritize patient breathing instructions based on this analysis.