From: Maruna, Thomas
Sent: Monday, February 24, 2014 6:55 PM
To: Daizadeh, Iraj (iraj_daizadeh@baxter.com)
Cc: Ananyeva, Natalya; Bhattacharyya, Lokesh
Subject: Information Requested: BLA 125512 Please Respond By March 18, 2014 
Importance: High
Baxter Healthcare Corporation
Attention: Iraj Daizadeh, PhD
February 24, 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 125512/0     Antihemophilic Factor (Recombinant), Porcine 
We have reviewed the following quality control assays for the drug product and their validation and method transfer reports submitted for STN 125512/0; we have determined that the following information is necessary to continue our review:
1. Determination of rp-FVIII Activity by Chromogenic Assay
a. Please provide the SOPs TQC-004.04 ----(b)(4)----- and ----(b)(4)-------------------- for determination of Factor VIII by chromogenic assay (also requested on 31 January 2014).
b. Please address the following questions regarding your Analytical Procedure [Potency-Chromogenic Assay] (3.2.P.5.2).
i. In the Methods section, please specify the dilutions which will be made of controls and samples for analysis. 
ii. In the System Suitability section, it states “The average activity control must be within pre-determined limits”. Please specify the acceptable range of the control.
c. You propose to use an in-house reference standard, ---(b)(4)----, in your routine lot-release testing (3.2.P.5.2). In section 3.2.S.5: Ref Std or Materials, you mentioned that the suitability of this standard was established based on a collaborative study between 5 labs and WHO 8th IS for VIII (07/350) was used as the standard in the collaborative study. Please provide data from this collaborative study to show that the in-house reference standard, ---(b)(4)-------, is adequately qualified for this assay. If data from the collaborative study is not available, please provide qualification data generated in your laboratory using an appropriate international standard.
d. We have the following IR questions/comments regarding your Method Validation Report, VR-105, and Technical Report, TCR-05-009.
i. You propose to use the in-house reference standard, ---(b)(4)-------, in your routine lot-release testing. However, this standard has not been used in evaluating any of the validation characteristics. Please provide data on all of the validation characteristics using the in-house reference standard that you propose to use in routine lot release.
ii. The Materials and Methods section in the Technical Report TCR-05-009 lists -------------(b)(4)-------------------------------------, while the Analytical Procedure 3.2.P.5.2 lists the concentration as (b)(4). Please clarify or amend accordingly.
iii. Stability studies (sections 5.1 and 5.2) and range determination (section 5.4) in the Validation Report VR-105 were carried out using --(b)(4)--, a reference standard for Phase 1 and Phase 2 clinical Drug Product batches, and not final Drug Product. Please provide a detailed description of ---(b)(4)-- and explain why we can consider this standard as a representative final container Drug Product. 
iv. In assessing specificity (section 5.3) in your Validation Report, VR-105, you spiked in-process samples with ---(b)(4)--- standard. When in-process samples are spiked with ---(b)(4)--- standard, the resulting sample does not represent the matrix of either the final container sample or the in-process sample. Please provide data using in-process and final Drug Product samples spiked with the reference standard that you intend to use in your routine lot-release testing ---(b)(4)---. We suggest that you spike the samples with the available international standards.
v. With reference to the specificity study in the technical report TCR-05-009, please provide details of the reference material used to spike the (b)(4) in-process samples. 
vi. In section 5.5 of VR-105, Intermediate Precision and Reproducibility, two data values are presented for Check Std and QCC-05-0103 in some cells of Tables 5.5.1 (page 10 of VR – 105) and 5.5.6 (page 11 of the same report). For example, you included 1.02/0.97 in the second row/second column of Table 5.5.1. Please explain why two data values are included. 
vii. Statistical analyses of the results for reproducibility in section 6.6 of VR-105 state, “Statistical comparison of the FDP results fails to reject the null hypothesis, and the means are equal with 95% confidence.” However, in Attachment 2, comparison of reproducibility of lots (b)(4)-- and (b)(4)--, you show statistically significant difference in measurement of lot (b)(4)-- (P-value (b)(4)) between the two laboratories and you concluded that “equality is not as strong”. Your null hypothesis is that variances between the two labs are the same (equivalency). We do not agree that failing to reject a null hypothesis of equivalency establishes equivalency between the two results. Please submit statistical analysis of your data showing that a null hypothesis of non-equivalency is rejected. 
2. Determination of Potency by One-Stage Coagulation Assay
a. Please provide the document 114102-SOP: One Stage Coagulation Assay using -----(b)(4)---------------- for OBI-1 (also requested on 31 January 2014).
b. Please address the following questions regarding your Analytical Procedure [Potency – One Stage Coagulation Assay] (3.2.P.5.2).
i. In the Method section, the control sample is defined as OBI-1 Control. Please describe the difference between the OBI-1 Control and the OBI-1 reference standard, including the detailed compositions of both materials. 
c. We have the following IR questions/comments regarding your Method Validation Report, 114393-RPT/1.0.
i. Accuracy (section 4.1), experiment was done using reference standard ---(b)(4)------- (DP) and not “validation sample” as was defined in section 3.3, that Batch (b)(4)-- of OBI-1 was used during execution of validation protocol, 114165-PTL. Please provide data for the validation sample.
ii. The validated range of the assay, ---(b)(4)-------, was set using reference standard and not validation sample (Batch (b)(4)-- of OBI-1). Please provide data for the validation sample. 
iii. You indicated in section 6: Linearity that linearity was assessed using OBI-1 drug product. However, in section 6.1: Procedure, you indicated that OBI-1 reference was diluted to obtain concentrations in the range of ---(b)(4)----. Please explain this discrepancy. Please provide linearity data with the standard and the Drug Product over the proposed assay range and demonstrate parallelism between the standard and the Drug Product.
iv. Your results in section 9: Robustness show that glass containers should be used for sample preparation. Please revise your SOP (document 114102-SOP) to clarify this requirement. 
3. Analysis of rp-FVIII Purity by -------(b)(4)----------------------
a. Please provide a copy of the document TCR-06-002 for precision studies in the test method transfer.
b. In Accuracy determinations shown in Table 13 and Figure 7 on page 16 of document VAP-VR-127, only one concentration of Drug Product has been used. Please provide accuracy data over the proposed range of the assay. We suggest that you evaluate accuracy at the minimum at 3 concentrations over the range of the assay and with 3 replicates at each concentration, as recommended by the ICH guideline Q2(R1).
4. Analysis of rp-FVIII Identity by ------------------(b)(4)--------------------------------- 
a. ------------------------------------------------------------------------------------------------------------------(b)(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
5. Determination of Sodium and Calcium by (b)(4)
a. We have the following IR questions/comments regarding your Method Validation Report, 042142-01-01
i. You have assessed linearity (sections 3.3) by analyzing calcium and sodium standards prepared in water at different concentrations. Please provide the linearity data for both sodium and calcium including linear regression plots, using representative final container product samples and demonstrate parallelism between the standard and final container product sample regression lines. 
ii. Please provide data to support the assay range (sections 3.3) by linearity, accuracy and precision studies obtained using representative final container product samples, evaluated at the minimum (b)(4)-- of the proposed specification range using at least three data points in the required range for both sodium and calcium. 
iii. In Table 3-10 (repeatability), the mean calcium and sodium concentrations are -----(b)(4)--------------, respectively. It appears that the column for sodium represents the concentration of calcium and vice versa in the table. Please verify and revise the table, if necessary.
iv. Precision (both repeatability and intermediate precision) for sodium and calcium was evaluated using ----(b)(4)------- containing significantly higher levels of sodium and calcium than the specification range for the final container Drug Product samples. Please provide data for repeatability and intermediate precision using representative final container Drug Product samples.
v. Page 28 (robustness) states under Conclusion, “Results show that the method is robust to small variations in mobile phase, gradient program……” Please explain how you inferred this conclusion from the data provided in Tables 3-14 and 3-15. Please define with justification criteria for acceptable difference 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 March 18, 2014 referencing the date of this request.
If it is not feasible for Baxter to provide all responses by March 18th, Baxter may provide a partial response and indicate the new date for the rest of responses.
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 
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