From: Maruna, Thomas
Sent: Tuesday, April 01, 2014 3:23 PM
To: Daizadeh, Iraj (iraj_daizadeh@baxter.com)
Cc: Ananyeva, Natalya; Del-Grosso, Alfred
Subject: Information Requested: BLA 125512 Please Respond By May 15, 2014
Importance: High
Baxter Healthcare Corporation
Attention: Iraj Daizadeh, PhD
April 1, 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. Regarding Validation report of the method for the determination of Water Content in rpFVIII Drug Product (AMV-MVR(1)-M002/M008, 112835-RPT/1.0,114328-RPT/1.0):

o As described in the report, the linearity of this assay has apparently been demonstrated only with standard solutions containing water. Please provide linearity results in product matrix along with a comparison of linear-regression results in product matrix with those obtained with standards.

o The Limit of Quantitation (LOQ) was evaluated using standard solutions. Please provide LOQ results based on an evaluation in product matrix. LOQ may be established as the lowest concentration for which accuracy and precision have been adequately evaluated in product matrix.

2. Regarding Validation of the method for Polysorbate 80 in OBI-1 by ------(b)(4)-------------------------- (114326-RPT/1.0, 11687-RPT/1.0):

o The linearity of this assay was demonstrated only with standards. Please provide linearity results in product matrix along with a comparison of linear-regression results in product matrix with those obtained with standards. 

3. Regarding the assays and validations for sucrose, Tris (trishydroxymethylamino-methane), chloride, citrate, sodium and calcium: 

o The validation reports were prepared by (b)(4). Please provide the locations where validations were conducted and where lot release testing is to be performed. If methods have been transferred between laboratories, please provide transfer reports to demonstrate acceptable comparability at the different locations. 

4. Regarding the Analysis of Tris in rp-FVIII (OBI-1) ------(b)(4)-----------, Lyophilized Finished Product, ---------------------------------------(b)(4)------------------------------------------------------------------------------------------------------------------------------------------------:

o -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------. 
[(b)(4)]
o Regarding the validation report (b)(4) 042142-01-04: 

a. In the sample and standard solution stability study in Section 3.8 of the validation report, it was concluded that derivatized sample and standard solutions are only stable within the same day of preparation. SOP version 03, Section 10 currently states that --------------------(b)(4)---------------------------------------------------. Please submit a updated SOP specifying that standards and samples are to be analyzed the same day as prepared. 

b. In the intermediate precision study described in validation report Section 3.6.2, high variability in the mean Tris values between two analysts was observed, -----(b)(4)------------------ respectively. It was concluded that the likely cause was related to time following derivatization in that the first analyst derivatized standards on one day and samples on another. Please submit intermediate precision data in which analysts perform derivatization the same day as analysis as is specified in the current procedure.

5. Regarding the Analysis of Sucrose in rp-FVIII (OBI-1) -----------(b)(4)----------------, Lyophilized Finished Product, ----------------------(b)(4)--------------------------------------------------------------------------------------:

o The method describes a polynomial fit for the standard calibration. Please provide an evaluation of linearity in product matrix along with an evaluation of parallelism of the analyte response as standards and in matrix. 

o Please add a low limit for the tailing factor in section 12.4 besides the high limit (b)(4) in the SOP P13864.01.

o Please justify the acceptance criterion for -------------------(b)(4)--------------------------------- in section 12.5 of the SOP. If historical data indicates that higher theoretical (b)(4) values were found during validation and routine use of the method, please reset this criterion and resubmit for review.

o In the current validation report ((b)(4) 042142-01-03), precision has only been evaluated at a concentration level of approximately --(b)(4)--. This is higher than the drug product specification range of ---(b)(4)-------.Please provide data for repeatability and intermediate precision at levels within this specification range.

6. Regarding the Assay for Chloride and Citrate by -------(b)(4)---------------------------- 

o As described in validation report (b)(4) 042142-01-02, linearity for both chloride and citrate was validated using standard solutions in water. The linearity of the assay should be evaluated in sample matrix. Please provide validation data for linearity using standard spiked placebo or drug product.

o The validation summary (page 8) states that “the range of ----(b)(4)-------- of the nominal chloride method concentration, -(b)(4)-- is supported by the linearity, accuracy and precision data”. Pages 25 and 27 describe data obtained from a sample with results of --(b)(4)-- for repeatability and -(b)(4)-- for intermediate precision. The drug product specification for chloride is proposed as ---(b)(4)------. Please explain how these values relate to the drug product specifications. If precision data has not been obtained for samples within the drug product specifications, please perform and submit these study results.
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 15, 2014 referencing the date of this request.
If it is not feasible for Baxter to provide all responses by May 15th, 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." 

