CELLTRION, Inc.: Steqeyma

We acknowledge receipt of your resubmission dated October 16, 2024, which constituted a complete response to our September 30, 2024, action letter.

For administrative purposes, we have split BLA 761338 as follows:

The subject of this correspondence is BLA 761338/Original 2. A separate correspondence was issued for BLA 761338/Original 1.

This provisional determination is based upon information available to the Agency at this time (i.e., information in your application and that the manufacturing of the biological product complies with the standards established in the BLA as well as the requirements in applicable regulations).

In addition to a safety update, the amendment should also identify changes, if any, in the application, i.e., updated labeling; chemistry, manufacturing, and controls data; and risk evaluation and mitigation strategy (REMS).

We remind you of your postmarketing commitments:

Submit nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing final reports to this BLA. In addition, under 21 CFR 601.70 you should include a status summary of each commitment in your annual progress report of postmarketing studies to this BLA.

Methods Validation for Drugs and Biologics (2015)", for non-compendial method, validation data are needed to support the reproducibility of the method.

You provided the stability data under the accelerated 2 condition using representative DP lots to support the labeled inuse storage for CT-P43 at room temperature prior to administration or dilution.

In addition, to further support the in-use dilution stability of the 130 mg/26 mL single-dose vial CT-P43 drug product and as recommended per ICH Q1A(R2), provide additional in-use stability testing of end of shelf-life DP vial samples after the maximum "days room temperature storage.

Revise the quality information amendment to provide accurate and complete responses to the quality information request dated May 3, 2024, in your BLA re-submission.

The facility should provide satisfactory responses to these deficiencies to the FDA office indicated on the FDA 483 prior to your complete response to your application.

Your complete response should include the date(s) of the facility's response to the FDA Form 483. The assessment of application approvability and the resolution of inspection deficiencies would be evaluated upon receipt of the complete response and may include re-inspection of the facility.

1. During a recent inspection of the Celltrion, Inc. (FEI 3005241015) manufacturing facility, the field investigator conveyed deficiencies to the representative of the facility.

3. To support the licensure of CT-P6 420 mg/vial, the CT-P6 DP manufacturing process and controls should be set to ensure the appropriate deliverable volume and protein concentration after reconstitution in each DP vial to meet the label claim.

Section 3.2.P.2.2) and fill weight limits ( © mg: Section 3.2.P.3.4) were provided in the BLA to support fill volume/weight control strategy.

1. You have submitted 6-month storage stability data for CT-P6 and US-licensed Herceptin in human serum (Project RFHD2).

The 6-month storage stability data does not support the sample analysis using ELISA method (ICD546) for Study CT-P6 1.5, which was around 18-months in duration.

The acceptability of your updated control strategy (process parameters and associated acceptable ranges) for lyophilization will be a review issue that will be addressed in the next review cycle upon receipt of your resubmission.

During a recent inspection of the Celltrion, Inc. (FEI 3005241015) manufacturing facility, our field investigator conveyed deficiencies to the representative of the facility.

Satisfactory resolution of the deficiencies is required before this BLA may be approved.

You have not provided adequate information and scientific justification that Study CT-P10 3.3, in patients with advanced follicular lymphoma, is adequate to detect differences between the products, should they exist, to support a demonstration of no clinically meaningful differences between CT-P10 and US-licensed Rituxan in terms of the safety, purity, and potency of the product.

3. In the responses received on November 21 and 28, 2017, to the Agency's information request (IR) comments le, 1f, li and 16 dated November 13, 2017, Celltrion included descriptions of certain process parameters.

8. In the response to IR comment 4 received on January 3, 2018, Celltrion described the stability testing plan and specifications for the CT-P10 master and working cell banks;

December 21, 2017, indicates that a small portion of the 100 mg CT-P10 DP vials from the PPQ and commercial runs fail based on © 11 weight check and these vials do not meet the requirement of extractable volume per USP<1>.

14. Information and data supporting the use of the drug product sterilizing filter is insufficient.

The bacterial retention study data included in the BLA showed a loss in cell viability after 8 hours of contact with the drug product.

Provide bacterial growth study data to demonstrate consistent growth of B. diminuta for up to 8 hours of contact time with the drug product.

2. Inthe complete response submission, provide updated data from the following studies that are ongoing:

3. Results from the endotoxin spiking study indicate that the CT-P10 drug product is affected by low endotoxin recovery (LER) when tested using the kinetic chromogenic method.

Therefore, the applicant submitted data to qualify the Gel Clot method as an alternative method for endotoxin detection.

If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under 21 CFR 601.3(c).