AFT Pharmaceuticals Ltd.: sirolimus

The following CMC comments/recommendations that are not approvability issues should be addressed in your resubmission:

June 21, 2022, which was not reviewed for this action.

The risk assessment should be based on the maximum level of each leachable expected to be present in the drug product based upon the analysis of the data from your long-term stability samples.

Please refer to your new drug application (NDA) dated and received March 1, 2017, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Combogesic (acetaminophen and ibuprofen) tablets.

Currently, the need for a facility inspection, and an assessment of the findings, is the only deficiency with your application.

"Recommended Dosage: See prescribing information for full dosage information."

Supply Chain Security Act.a The Act requires manufacturers and repackagers, respectively, to affix or imprint a product identifier to each package and homogenous case of a product intended to be introduced in a transaction in(to) commerce beginning November 27, 2017, and November 27, 2018, respectively.

Act for COMBOGESIC (ibuprofen 97.5 mg/acetaminophen 325 mg) Film-Coated Tablets.

We also acknowledge receipt of your amendment dated November 22, 2017, which was not reviewed for this action.

In a response from you dated June 13, 2017, you acknowledged the derivation of these datasets were generated manually within Microsoft Excel, which produced errors in the datasets submitted to the NDA. To address this concern, you proposed the following:

1. The sponsor will contract a third party to produce SAS programs to reproduce the primary and secondary analyses from the submitted ADaM domains.

2. As an extra level of confirmation, for complete traceability, the sponsor will contract a third party to produce SAS programs for the derivation of new ADaM datasets as well as primary and secondary endpoint analyses from the submitted SDTM domains.

However, your amendment dated November 22, 2017, was not reviewed for this action.

7. The drug product regulatory specifications which include all required quality attributes and their corresponding acceptance limits have not been provided.

To address this deficiency, provide the final regulatory acceptance limits and tests for the release and stability of the drug product.

To address this deficiency, provide a certification to demonstrate that the lactose used as an excipient in the drug product complies to the BSE/TSE regulations.

Spongiform Encephalopathy (BSE) in FDA-Regulated Products for Human Use," located at:

Submit draft carton and container labeling revised as follows when you resubmit your application:

We recommend you add the lot number to the carton labeling in accordance with 21 CFR 201.10(i)(1) and relocate the other numbers (BN, GTIN, and Sr. No) away from the lot number to avoid confusing the lot number with these other numbers."

However, the Pediatric Research Equity Act (PREA) requires a pediatric assessment for indications for which sponsors are receiving or seeking approval in adults, unless the requirement was waived or deferred.

Potential sections of COMBOGESIC labeling.

Submit the following information when you respond to the Complete Response Letter.

The entire ITT population should be included in data analyses incorporating missing data management.

4. Provide results of analyses of treatment differences between each active treatment and placebo for the primary endpoint in addition to comparing treatment differences between the drug combination and each of the other three treatments.

For patients who had perceptible PR within the first six hours not followed by meaningful PR any time afterwards within the first six ours, time to onset should be censored to six hours and the entire ITT population should e included in data analyses.

7. Provide a summary for single-dose duration in terms of median time to rescue and/or remedication (second dose of study medication) by the end of the first dosing interval, including censored data and covering the entire ITT population.