From: Maruna, Thomas
Sent: Wednesday, August 06, 2014 1:07 PM
To: Daizadeh, Iraj (iraj_daizadeh@baxter.com)
Cc: Bhattacharyya, Lokesh; Ananyeva, Natalya
Subject: Information Requested: BLA 125512/0 Please Respond By August 25, 2014
Importance: High
Baxter Healthcare Corporation
Attention: Iraj Daizadeh, PhD
August 6, 2014
Sent by email 
Dear Dr. Daizadeh:
We are reviewing your November 25, 2013 biologics license application (BLA) indicated for the treatment and prevention of bleeding episodes in patients with acquired inhibitory antibodies to human factor VIII (i.e., acquired hemophilia patients) for the following:
STN             Name of Biological Products
BL 125512   Antihemophilic Factor (Recombinant), Porcine Sequence
We determined that the following information is necessary to continue our review: 
1. Determination of rp-FVIII Activity by Chromogenic Assay 
We have reviewed your response to our Information Request (IR), dated 17 April 2014, and have the following additional requests for information.
a. In response to our Question 1c, you acknowledged that the method used was circular and provided additional qualification data in the report ID # TCR-05-009. However, we found that you used the same material as the reference standard and the sample ---(b)(4)- to generate the data for the low point ((b)(4) of the target concentration) (Figure 3 of the report ID # TCR-05-009). This is still circular. In addition, your accuracy results do not cover the necessary (b)(4)--- of the target concentration range. Please provide data to support the range using a lot of Final Drug Product that is different from the reference standard at --------(b)(4)--------------------- of the target value of the drug, as requested in our previous IR.
b. In response to our Question 1d, you referred to Table 2 of the document # VR-105 to indicate that you evaluated potency in the (b)(4)---- of target analyte potency range. However these experiments were performed using the same lot of product as both the reference standard and the sample, which is circular, hence the IR has not been addressed adequately. Please evaluate linearity and precision at ---(b)(4)------ of the target potency, as requested in the previous IR. 
c. In response to our Question 1e, you stated that the reference standard, ---(b)(4)-------, is no longer available, and that this standard was calibrated against the reference standard (b)(4). Have you qualified (b)(4) against an International Standard? If, yes, please provide the qualification data. If not, please address the authenticity of (b)(4). This is critical because you have conducted all your validation experiments using the standard (b)(4), however, you will be using a different standard for routine lot release and stability studies. Therefore, it is critical to establish equivalency between the standard used during method validation and routine use. 
2. Analysis of Sucrose in rp-FVIII (OBI-1) -------------(b)(4)------------------------, Lyophilized Finished Product, -------------------(b)(4)------------------------------------------------------
We have reviewed your response to our IR, dated 1 April 2014, and have the following additional requests for information.
a. In question #5 we requested, “Please justify the acceptance criterion for ---------------(b)(4)------------------ in section 12.5 of the SOP. If historical data indicates that ---------(b)(4)--------------------------- were found during validation and routine use of the method, please reset this criterion and resubmit for review.” To this date, we have not received your response. Please provide the information as requested as soon as possible.
b. In Amendment 19 (dated May 9, 2014), you indicated that you would submit by 30 June 2014 report/data from two supplemental validation studies on linearity and precision/range for the test method. However, we have not received these reports yet. Please provide the data as soon as possible. 
c. In Amendment 19 (dated May 9, 2014), you indicated that you would submit updated versions of the following SOPs:
SOP M2936.05: Method for the Analysis of Sucrose in rp-FVIII (OBI-1) ----------(b)(4)---------------- Lyophilized Finished Product, ---------------(b)(4)-------------------------------------------------------------------------------
SOP M2937.05: Method for the Analysis of Tris in rp-FVIII (OBI-1) -----------(b)(4)-------------, Lyophilized Finished Product, -------------------------(b)(4)------------------------------------------------------------------------------------------------
We have not received the updated versions of these two SOPs yet. Please provide them as soon as possible.
3. Determination of Sodium and Calcium by (b)(4)
We have reviewed your response to our IR, dated 17 April 2014, and have the following additional requests for information.
a. In response to our question 4a, you indicated that you would provide the requested data by 30 June 2014. We have not received the data yet. Please provide the data as soon as possible. 
b. We reviewed your experiment plan in response to our question 4a to evaluate linearity, precision and accuracy. We could not understand how your planned experiments could lead to an inference of accuracy. The necessary linearity experiment required to “infer” accuracy, e.g., parallelism between response vs analyte concentration (or dilution) curves for the standard and the sample, was not included in the study plan. Please explain how you would obtain an inference of accuracy based on the plan you provided.
Please provide your complete responses by August 25, 2014. 
Please note that the FDA is under no commitment to review the information submitted after this cut-off date. 
The review of this submission is on-going and issues may be added, expanded upon, or modified as we continue to review this submission. 
The action due date for these files is October 25, 2014.
If you have any questions, please contact me at (240) 402-8454 or thomas.maruna@fda.hhs.gov (preferred).
Very Respectfully,
Thomas J. Maruna, MSc, MLS(ASCP)CM
Lieutenant, U.S. Public Health Service
Senior Regulatory Management Officer
Food and Drug Administration
Center for Biologics Evaluation and Research
Office of Blood Research and Review
10903 New Hampshire Ave.
Silver Spring, MD 20993
thomas.maruna@fda.hhs.gov
O: (240) 402-8454
www.usphs.gov 
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