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Vaccines, Blood & Biologics

Complete Response Letter, Mr. Vaughn - Bivigam

DEPARTMENT OF HEALTH & HUMAN SERVICES                                                     Public Health Service


                                                                                                                            Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448



Our STN: BL 125389/0
Biotest Pharmaceuticals Corporation
Attention: Matthew Vaughn
5800 Park of Commerce Blvd. NW
Boca Raton, FL  33487
Dear Mr. Vaughn:
This letter is in regard to your biologics license application (BLA) for Immune Globulin Intravenous (Human), manufactured at your Boca Raton, Florida location, 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:
    1. Your Testing Plan and Lot Release Protocols have not been finalized.
    1. 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.
  1. 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 demonstrate experimentally that virus would be detected at the theoretical limit of detection in a (b)(4) format when the assay is used for the following viruses: HIV, PRV, BVDV, SinV, and SV40.
  1. -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------.
  1. You have not included in your 100% visual inspection program for Biotest IGIV (as previously requested), a complete description of the defect set used to qualify (b)(4) inspectors for Biotest IGIV final product, nor have you submitted all validation data supporting --(b)(4)-- 100 % visual inspection program for this product.  Please submit both a complete description of the defect set, and all supportive validation data.
  1. Cleaning validation is not adequate in that:
a.      Your use of a ---(b)(4)--- cleaning validation limit of -----(b)(4)----- is not appropriate for cleaning validation for equipment utilized in downstream process steps (b)(4), as use of this criterion would allow carryover of residual cleaning agents.  Please reevaluate use of this cleaning validation acceptance criterion, select a criterion that would not allow for significant carryover of cleaning agent, and submit validation data demonstrating that you can meet the new acceptance criterion.
b.     Your cleaning validation acceptance criteria do not reflect cleaning process capability, as actual values observed during validation were well below set acceptance criteria.  Please evaluate actual data obtained during cleaning validation studies, and set cleaning validation acceptance criteria that reflect your process capabilities.
c.      Your use of a family approach to cleaning validation allows for introduction of equipment that has not yet been evaluated for clean ability, in that you do not perform at least one cleaning validation run for each piece of equipment within each family.  Please perform at least one cleaning validation run for the following equipment: ------------------------------(b)(4)---------------------------------------------- certain miscellaneous equipment (--------------------------------------(b)(4)----------------------- etc.) and submit the results of these runs for review.
  1. You have not performed a bulk drug product shipping validation study that utilizes actual shipper, containers, and modes of transportation normally employed to transport product. Please perform the study and submit the results for review.
  1. The toxicology assessment of the -------------(b)(4)---------------- does not contain an assessment of the potential human exposure to leachables from the (b)(4).  Please submit a toxicological assessment that includes a worst case scenario exposure of human subjects to these compounds and demonstrates that, even at these exposures, appropriate safety factors are in place to ensure safety of all subjects.
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 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, 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.
Sincerely yours,
Basil Golding, M.D.
Division of Hematology
Office of Blood Research and Review
Center for Biologics
 Evaluation and Research

Page Last Updated: 09/23/2013
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