Kashiv BioSciences, LLC: TPI-120

0025), to support that the filling line operations for the manufacture of the drug product on ee ranean are appropriately controlled and can result in a product wi consistent protein concentration.

= provide data and wtormation ° support that the conto m allows for the consistent and accurate fill volume for the drug product.

While your firm's vendor, appears to have tested activation force to demonstrate a confidence and reliability of 95/99%, the testing does not appear to have been conducted with the to-be-marketed configuration of TPI-120 containing the TPI-120 drug solution.

Please ensure forces are evaluated after sequential shelf-life, shipping, and drop/freefall, with final finished combination product, utilizing a variable method that is representative of forces that a user would experience to activate the needle guard (i.e., measured after depressing the drug product out of the syringe), meeting a confidence and reliability of 95/99%.

For this purpose, first-cycle actions include approvals, complete responses, and withdrawals after filing.

Due to U.S. Government and/or Agency-wide restrictions on travel, we were unable to conduct an inspection of the Kashiv Biosciences LLC facility during the current review cycle, and the application cannot be approved until the required FDA inspection is conducted and the findings are assessed with regard to this application.

In-House Working Reference Standard Lot " as an update to the information request response #3 dated October 08, (BLA 761082/0053).

To ensure that the proposed change has no impact on the potency assay method validation and test article data, provide adequate information to support the proposed change.

As stated in our February 7, 2017 BPD Type 4 meeting to discuss the content of format of the BLA, we stated that you should include expellable volume testing at the end of your proposed shelf life.

3011289655), Chicago, Illinois, is required before this application can be approved as the FDA must assess the ability of that facility to conduct the listed manufacturing operations in compliance with CGMP.

Disease 2019 (COVID-19) public health emergency."

3. In your response to the June 11, 2019, complete response (CR) item # 3, you reported the detection of two sequence variants, S77-R77 and G101-R101 from a peak (CEX-P6) separated using the CEX-HPLC method.

We acknowledge that you provided data to support that the removal of kanamycin in tel nae fermentation processes does not have an impact on manufacturing process and product quality.

This replacement complete response letter incorporates the correction of the error.

The effective complete response date will remain June 11, 2019, the date of the previous complete response letter.

1. During a recent inspection of the Kashiv BioSciences, LLC (FEI 3011289655) manufacturing facility for this BLA, our field investigator conveyed deficiencies to the representative of the facility.

Satisfactory resolution of these deficiencies is required before this application may be approved.

In the absence of an adequately functioning QA unit, the Agency does not have sufficient assurance that the Applicant will be able to perform an appropriate retrospective review of all analytical data to ensure their accuracy.

To address this deficiency, identify an appropriately qualified, external third party to perform an independent and thorough audit of all the product quality data provided in your 351(k) BLA for accuracy and completeness.

The Agency recommends that, prior to initiating the external third party audit, you submit a detailed audit protocol with the following information to obtain Agency's agreement on the protocol design and content:

Depending on the final audit results, as appropriate, additional studies may be needed to generate new information and data to support the product quality content in your 351(k) BLA resubmission.

The Agency will not be able to perform a meaningful review of your 351(k) BLA until the final audit report provides assurance that all analytical similarity and other product quality information provided in the 351(k) BLA application is accurate and complete.

351(k) BLA resubmission to demonstrate why these differences do not preclude a determination that Theragrastim is highly similar to US-licensed Neupogen.

US-licensed Neupogen lot 1062643 with an expiration date of April 2018, were tested after expiry in this study.

In your 351(k) BLA resubmission, you stated that the conditions used in the original forced degradation study under protocol PTL-1192-R were too extreme.

24.Real time stability data provided in the BLA submission do not support the proposed 24 months dating period for Theragrastim PFS and vial presentations.

This DMF was found inadequate to support your submission and a deficiency letter was sent to the DMF holder on May 16, 2019. These deficiencies must be adequately addressed before this application can be approved.

As part of your response to this CR letter, include the date the DMF holder amended their DMF to address the deficiencies.

Clarify these discrepancies and provide the corrected information in the BLA resubmission.