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Vaccines, Blood & Biologics
Our STN: BL 125389/0
Biotest Pharmaceuticals Corporation
Attention: Gary Ingenito, M. D., Ph. D.
5800 Park of Commerce Blvd., N.W.
Boca Raton, FL 33487
Dear Dr. Ingenito:
This letter is in regard to your biologics license application (BLA) for Immune Globulin Intravenous (Human) manufactured at your Boca Raton, Florida location and submitted under section 351 of the Public Health Service Act (42 U.S.C. 262).
We have completed our review of all the submissions you have made relating to this BLA. After our complete review, we have concluded that we cannot grant final approval because of the deficiencies outlined below.
Chemistry Manufacturing and Controls (CMC) :
1. The validation of your Test Methods remains incomplete in that a proposal for the testing of -----(b)(4)-------------- of Bivigam has not been agreed to and finalized. This would involve the validation of a -----(b)(4)-------------- test or similar assay.
2. The viral clearance studies performed to support the adventitious agent removal/inactivation capabilities of your manufacturing process are inadequate as the assays used have not been fully validated. In order to complete the validation of your -----(b)(4)-----------------Assay, you must complete bridging studies between the ---(b)(4)---- format and the ---(b)(4)---- format for SinV and SV40 viruses.
3. Your reported bioburden results in your cleaning validation report exceeded the revised acceptance limit of ---(b)(4)------ for ----------------------------(b)(4)-------------------------------------. Please provide additional validation studies for the -(b)(4)- to support that your cleaning procedures are capable of reducing bioburden to meet the acceptance limit.
4. We noted that the ----(b)(4)------ solution interfered with your ------------(b)(4)---------------------- testing performed for the ----(b)(4)---- cleaning validation, and prevented you from demonstrating the ability of your cleaning process to remove product residual. Please perform residual protein analysis on ---(b)(4)------ post-cleaning rinse samples with appropriate acceptance criteria, and submit the data for review.
We stopped the review clock with the issuance of this letter. We will reset and start the review clock when we receive your complete response.
Within 10 days after the date of this letter, you should take one of the following actions: (1) amend the application; (2) notify us of your intent to file an amendment; or (3) withdraw the application.
You may request a meeting or teleconference with us to discuss the steps necessary for approval. For PDUFA products please submit your meeting request as described in our “Guidance for Industry: Formal Meetings With Sponsors and Applicants for PDUFA Products,” dated February 2000. This document is available on the internet at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079744.pdf or may be requested from the Office of Communication, Outreach, and Development, at (301) 827-1800. For non-PDUFA products, please contact the regulatory project manager. For details, please also follow the instructions described in CBER’s SOPP 8101.1: Scheduling and Conduct of Regulatory Review Meetings with Sponsors and Applicants. This document also is available on the internet at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm079448.htm, or may be requested from the Office of Communication, Outreach, and Development.
Please be advised that, as stated in 21 CFR 601.3(c), if we do not receive your complete response within one year of the date of this letter, we may consider your failure to resubmit to be a request to withdraw the application. Reasonable requests for an extension of time in which to resubmit will be granted. However, failure to resubmit the application within the extended time period may also be considered a request for withdrawal of the application.
If you have any questions regarding the above, please contact the Regulatory Project Manager, Pratibha Rana, at (301) 827-6124.
Basil Golding, M.D.
Division of Hematology
Office of Blood Research and Review
Center for Biologics
Evaluation and Research