From: Maruna, Thomas
Sent: Thursday, April 17, 2014 1:32 PM
To: Daizadeh, Iraj (iraj_daizadeh@baxter.com)
Cc: Ananyeva, Natalya; Bhattacharyya, Lokesh
Subject: Information Requested: BLA 125512 Please Respond by May 5, 2014 
Importance: High
Baxter Healthcare Corporation
Attention: Iraj Daizadeh, PhD
April 17, 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 have reviewed the following quality control assays for the drug product and their validation and method transfer reports submitted for STN 125512/0 as well as your subsequent submissions received on 13 February 2014 and 17 March 2014, and have the following Information Requests:
1. Determination of rp-FVIII Activity by Chromogenic Assay
a. You have demonstrated specificity of the assay by spiking known quantities of rpFVIII to in-process samples. Your data do not demonstrate specificity of the assay for the OBI-1 final container drug product (OBI-1 FCDP) because, although the FCDP contains more purified rpFVIII, it also contains additional excipients. Furthermore, FCDP is only -----(b)(4)--- in the assay buffer for potency measurements. Hence the effect of excipient on final drug product potency cannot be considered negligible due to dilution. Please provide data to demonstrate specificity in FCDP. We recommend that you also submit results of the assay of the Assay/Dilution Buffer showing negligible contribution from this buffer to demonstrate specificity of your assay. 
b. Please provide information on what material you used to spike rpFVIII to the in-process sample for the specificity study in document TCR-05-009. 
c. You evaluated range by assaying the reference standard at ------(b)(4)---------- of the target concentration. But you used the same material as the reference standard in this evaluation. This is circular. Please provide data to support range using a lot OBI-1 FCDP that is different from the reference standard.
d. You evaluated linearity, accuracy and precision at ----(b)(4)------------ of the target potency. Please provide data evaluating these validation characteristics either to cover the proposed assay range or (b)(4)-- of the target potency in the assay, whichever is wider.
e. Please provide comparability data showing that the two standards, -----(b)(4)------------- will produce equivalent results. Please provide data for at least 6 samples, preferably more. Also, please provide data showing dilution parallelism between the two standards.
f. Please revise your SOP to include the following and submit your revised SOP for review.
i. Details of dilution of the samples
ii. Acceptable potency of the control for system suitability 
2. Determination of Potency by One Stage Coagulation Assay
a. Please provide qualification data for the Positive Control (OCC-13-0906) used in this assay.
b. You evaluated accuracy and range by assaying the reference standard at -----(b)(4)-------------- of the target concentration. But you used the same material as the reference standard in this evaluation. This is circular. Therefore, we do not agree that accuracy and range have been adequately evaluated. Please provide data to support range using a lot OBI-1 FCDP that is different from the reference standard.
c. Please provide data to demonstrate repeatability (precision) of the assay over the assay range. We suggest that you use at least three concentration levels.
d. Please revise your SOP to include acceptable potency of the control for system suitability.
e. In response to our previous IR (dated 24 February 2014) you indicated that parallelism data has been shown in sections 7 and 8 of your validation report (114393-RPT/1.0). We did not find the data and their analyses in these sections. Please provide the data and analyses to demonstrate parallelism between standard and FCDP samples. Also, please provide slopes, intercepts and distribution of residuals of the dilution curves of the standard and OBI-1 FCDP samples for the data presented in this section. 
3. Analysis of rp-FVIII Purity By ---------------(b)(4)---------------------------
a. In response to our previous IR (dated 24 February 2014) you indicated that you assessed accuracy in the supplemental validation report, 113226-RPT. We found that you used (b)(4). However, (b)(4) is not your product. Please provide accuracy data over the proposed range of the assay, as requested previously, using OBI- FCDP.
4. Determination of Sodium and Calcium by (b)(4)
a. In response to our previous IR (sent on 24 February 2014), in which we requested linearity and accuracy data in a matrix that will be representative of sodium and calcium in OBI-1 FCDP, you presented linearity and accuracy data obtained in a “Placebo buffers”, which, according to the information you provided, contains all matrix components of sodium and calcium, except OBI-1. Therefore, the “placebo buffer” does not present a representative matrix. These two metal ions interact with (and bind to) OBI-1. We requested data to ensure that your (b)(4) method could overcome the interaction/binding and provide accurate results of sodium and calcium (accuracy at different concentrations and linearity). The data you presented do not demonstrate this critical point. Please provide linearity and accuracy data for sodium and calcium in a matrix that will be representative of sodium and calcium in OBI-1 FCDP. The data should include results either to cover the proposed assay range or (b)(4) of the target analyte concentration, whichever is wider. It will be acceptable for us if you prepare a lab scale mock matrix formulation that is an appropriate representative matrix for sodium and calcium in OBI-1 FCDP and obtain data using the lab scale matrix.
b. In our previous IR, we requested linearity, accuracy, and precision data in support of your proposed range. As explained above, your accuracy and linearity data were not acceptable. In addition, you have not provided precision data as requested. Please provide appropriate accuracy, linearity and precision data to support the proposed assay ranges for each analyte.
c. In Section 3.7 of Method validation report 042142-01-01, the acceptance criteria for robustness states that “Compare all results with those obtained from the analysis using the original method parameters.” In our previous IR (sent on 24 February 2014), we asked how you inferred acceptance of the results. Your response, “The evaluation was conducted based on the effect on the sodium and/or calcium content” does not address the question adequately. Please define acceptable difference (in quantitative terms) in sodium and calcium concentrations relative to the value under original conditions.
The review of this submission is on-going and issues may be added, expanded upon, or modified as we continue to review this submission. 
Please submit your responses as an amendment to this file by May 5, 2014 referencing the date of this request.
If it is not feasible for Baxter to provide all responses by May 5th, please provide an alternative date to respond. 
The action due date for these files is July 26, 2014.
If you have any questions, please contact me at (301) 827-6120.
Very Respectfully,
Thomas J. Maruna, MSc, MLS(ASCP)CM
Lieutenant, U.S. Public Health Service
Senior Regulatory Management Officer
Food and Drug Administration
CBER/OBRR/DBA/RPMB
1401 Rockville Pike
RM 562N, HFM-380 
Rockville, MD 20852
thomas.maruna@fda.hhs.gov
O: (301) 827-6120
BB: (240) 397-3419
www.usphs.gov 
"THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER LAW. If you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any review, disclosure, dissemination, copying, or other action based on the content of this communication is not authorized. If you have received this document in error, please immediately notify the sender immediately by e-mail or phone." 

