Approval Letter Other 214375 (Jan 1, 2023)

The degree of polarization of xenon-129 hyperpolarized is a critical quality attribute of the drug component in your drug-device combination product. Establish specification and acceptance limits with tolerances (acceptable variation) with adequate justification per 21 CFR 314.50(d)(ii)(a). Include measurements from clinical batches of xenon-129 hyperpolarized produced by the device and proposed commercial batches produced by. Submit a table with batch results, batch identification number/date, and batch use (e.g., health center-clinical, registration, etc.).

Recommended response: Develop and justify comprehensive specifications and acceptance limits for xenon-129 polarization, supported by data from clinical and commercial batches.

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

Validate the production method of xenon-129 hyperpolarized using at least three different batches of gas blend on commercial hyperpolarizer. The registration batches of xenon-129 hyperpolarized must meet final drug specification and be produced according to the proposed regulatory commercial production process under cGMP with documented actual yield and % of theoretical yield. This is a requirement under 21 CFR Part 4 if adopting the streamlined approach and implementing 21 CFR Part 820 regulations as the quality system. Submit to the application the master batch record and executed batch records for production of xenon-129 hyperpolarized from hyperpolarizer manufactured.

Recommended response: Conduct and submit validation data for the xenon-129 production method using commercial-scale processes under cGMP, including master and executed batch records.

Cited: 21 CFR Part 4, 21 CFR Part 820

Propose a strength for the drug product xenon-129 hyperpolarized, e.g., range of percent xenon-129 enrichment and range of percent hyperpolarization per volume.

Recommended response: Define and propose a clear strength for the drug product, including enrichment and hyperpolarization ranges.

Provide the final approval procedure along with approved release documents that will be reviewed and approved by Polarean for release of the finished devices.

Recommended response: Submit a detailed final approval procedure and associated release documents for finished devices.

Provide a comparative list of all the changes of the Hyperpolarizer and provide verification protocol/testing data for each of the changes to support the design changes. Provide detailed description for the change along with its material characteristics and its comparative analysis with the used for clinical studies.

Recommended response: Submit a comprehensive list of all Hyperpolarizer design changes, including verification data and a comparative analysis with the device used in clinical studies.

You have failed to provide reliability assessment reports for the Hyperpolarizer and the QC Measurement system. Submit the verification protocol, analytical tests/ methods, specifications and acceptance criteria, and final report for review and approval to support the annual calibration period and any proposed recertifications.

Recommended response: Provide complete reliability assessment reports for both the Hyperpolarizer and the QC Measurement system, including verification protocols and final reports.

During a recent inspection of the Polarean Inc. (FEI:3010132318) manufacturing facility for this application, our field investigator conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this application may be approved. (Similar deficiencies noted for other facilities).

Recommended response: Address and resolve all deficiencies identified during the manufacturing facility inspections and provide evidence of satisfactory resolution.

We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the Prescription Drug Labeling Resources and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) − a checklist of important format items from labeling regulations and guidances. If you revise labeling, use the SRPI checklist to ensure that the Prescribing Information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as described at FDA.gov.

Recommended response: Review and update labeling according to FDA guidelines and regulations once other deficiencies are resolved, ensuring compliance with SPL format and SRPI checklist.

Cited: 21 CFR 314.50(l)(1)(i)

Please refer to correspondence dated, December 29, 2020, which addresses the proposed proprietary name, Xenoview. This name was found acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

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

When you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the product under consideration regardless of indication, dosage form, or dose level. (Details follow on what to include).

Recommended response: Prepare a comprehensive safety update covering all nonclinical and clinical data as per 21 CFR 314.50(d)(5)(vi)(b) for inclusion in the resubmission.

Cited: 21 CFR 314.50(d)(5)(vi)(b)