Our STN: BL 125512/0                         LATE-CYCLE MEETING BACKGROUND PACKAGE
Baxter Healthcare Corporation
Attention: Mr. Iraj Daizadeh
One Baxter Parkway
Westlake Village, CA 91362
Dear Mr. Daizadeh:
Please refer to your Biologics License Application (BLA) submitted under section 351 of the Public Health Service Act for Antihemophilic Factor (Recombinant), Porcine Sequence [OBIZUR]. The proposed indication is for treatment and prevention of bleeding episodes in patients with acquired inhibitory antibodies to human Coagulation Factor VIII.
We also refer to the Late-Cycle Meeting scheduled for August 19, 2014. Attached is our background package, to include a review status update and an agenda for this meeting.
If you have any questions, please contact LT. Thomas J. Maruna, USPHS, MSc, MLS(ASCP)CM at (240) 402-8454.
Sincerely,
Basil Golding, MD
Director
Division of Hematology Research and Review
Office of Blood Research and Review 
Center for Biologics Evaluation and Research
ENCLOSURE:
Late-Cycle Meeting Background Package

LATE-CYCLE MEETING BACKGROUND PACKAGE
Meeting Date and Time: Tuesday, August 19, 2014; 3:30 PM – 5:00 PM EDT
Meeting Location: Federal Research Center at White Oak
10903 New Hampshire Avenue
Building 71, Room 1208/10
Silver Spring, MD 20993
Application Number: STN 125512/0
Product Name: Antihemophilic Factor (Recombinant), Porcine Sequence [OBIZUR] 
Indication: Treatment and prevention of bleeding episodes in patients with acquired inhibitory antibodies to human Coagulation Factor VIII
Applicant Name: Baxter Healthcare Corporation
INTRODUCTION
The purpose of a Late-Cycle Meeting (LCM) is to share information and to discuss any substantive review issues that we have identified to date, Advisory Committee (AC) meeting plans (if scheduled), and our objectives for the remainder of the review. The application has not yet been fully reviewed by the signatory authority, division director or chairperson, and therefore the meeting will not address the final regulatory decision for the application. We are sharing this material to promote a collaborative and successful discussion at the meeting.
During the meeting, we may discuss additional information that may be needed to address the identified issues, and whether it will be reviewed by the Agency in the current review cycle. If you submit any new information in response to the issues identified in this background package before this LCM, we may not be prepared to discuss that new information at this meeting.
SUBSTANTIVE ISSUES TO BE DISCUSSED AT THE LATE CYCLE MEETING:
CHEMISTRY, MANUFACTURING AND CONTROLS
1. Facilities and Equipment 
a. Please provide complete responses to observations in Forms FDA 483 issued at the Pre-License Inspections of Baxter’s ---(b)(4)---- facility and ----(b)(4)---------------- facility, including evidence of effectiveness of corrective actions. 
b. Please submit validation data for the lyophilizer at the --(b)(4)--- facility. Additional information may be requested after the validation package is submitted and reviewed. Please follow up on Question 4 in the February 14, 2014 Information Request (IR) and Item #1 in Form FDA 483.
c. Please provide summaries of shipping validation activities and results (including simulated studies, shipping studies with worst-case final packaging configurations and shipping conditions, etc.) for shipping of the ------(b)(4)----------------- from Baxter’s (b)(4)-- facility to ---------(b)(4)------ facility, and the filled Final Drug Product (FDP) from ---(b)(4)--------- facility to Baxter’s ----------(b)(4)---------------- facility. Please follow up on Question 7 in the February 14 IR and Item #4 in Form FDA 483.
d. Please submit an overview of the computer systems and validation status for ------(b)(4)------ facility.
e. Your summary report submitted on May 22, 2014 for the engineering testing run for labeling and packaging (new 3 mL format for OBIZUR) included a semi-automatic Visual Inspection step. Please note that the semi-automatic Visual Inspection process for a new vial format would require substantially more data to support its approval. You have a validated manual Visual Inspection process at ----(b)(4)------ facility. For the purpose of this BLA, please clarify whether the Visual Inspection of lyophilized vial will be performed manually at ---(b)(4)--------- facility or semi-automatically at Baxter’s -(b)(4) facility. Please follow up on Question 7 in the February 14, 2014 IR.
f. Please clarify whether Identity Testing of FDP is performed before and after labeling at Baxter’s ------(b)(4)------------------- facility. Please clarify whether or not the Identity Test is validated, the same as that submitted in the BLA, and performed at the same site as that of the release tests. Please follow up on Question 8 in the February 14 IR.
g. Please note that --------------(b)(4)---------------------- facility is currently used only for the manufacturing of OBIZUR. If you decide to introduce other products into this facility after its licensure, an appropriate regulatory submission is required to report this change. 
2. In-Support Testing
The Division of Biological Standards and Quality Control (DBSQC) cannot complete the in-support testing of FDP lots for Potency because the results by the Chromogenic assay for lots -------(b)(4)------------ at release and for all five lots at the most recent testing point have not been submitted by Baxter. Please follow up on the June 10, 2014 IR.
3. Analytical Methodology
Your responses to the April 17, 2014 IR, in the May 5, 2014 Amendment, are deemed incomplete. Please respond to the IR related to the validation of some analytical methods sent on August 6, 2014. 
4. Specification
Please revise/verify the acceptance limits for the parameter -----(b)(4)---------------------- based on separate analyses of the release and stability data. Please follow up on Question 3 in the May 12, 2014 IR, our discussion at ----(b)(4)-------------------- facility, and your commitment in the May 22, 2014 Amendment.
5. Stability
a. Please submit an update on sections 1 – 3 of Module 3.2.P.8 Stability, Drug Product, and related reports. Please include the re-integrated ---(b)(4)------- data for the Process Validation batches based on the criteria set for the commercial product, and the results of in-use stability study for the reconstituted product (Process Validation batches). Please follow up on Question 4 in the May 12 IR, May 22 Amendment, and your commitment made during the June 9, 2014 teleconference.
b. Please revise the Stability Program for Drug Product (Module 3.2.P.8.2) to include Container and Closure Integrity testing at all intermediate time-points. Please also include Sterility and Endotoxin testing at 12 months, the end of the proposed shelf-life (24 months) and the end of the study ---(b)(4)---------. 
6. Adventitious Agents Safety Evaluation
Baxter’s responses in the April 25, 2014 Amendment to the April 4, 2014 Information Request appear adequate. There are no substantive review issues at this time.
NON-CLINICAL PHARMACOLOGY / TOXICOLOGY
There are no substantive review issues at this time.
CLINICAL PHARMACOLOGY
There are no substantive review issues at this time.
CLINICAL
There are no substantive review issues at this time. 
* Please submit the Final Study Report for Pivotal Clinical Trial OBI-1-301/301a with additional safety and efficacy data for the 11 remaining subjects enrolled. 
BIORESEARCH MONITORING
There are no substantive issues at this time.
PHARMACOVIGILANCE
There are no substantive review issues at this time.
LABELING
* APLB will perform a secondary review of the proprietary name, OBIZUR, within 90 days of the Action Due Date.
* Recommendations to the Prescribing Information and the vial and carton labels will be provided as part of the labeling review. 
ADVISORY COMMITTEE MEETING
Presentation of the BLA at the Blood Products Advisory Committee meeting is not planned.
REMS OR OTHER RISK MANAGEMENT ACTIONS
No issues were identified that would require a Risk Evaluation Mitigation Strategy (REMS).
PMC/PMR
No issues have been identified at this time that would require a Post-Marketing Requirement. The need for a Post-Marketing Commitment(s) will depend on your responses to the inspectional items and outstanding IRs. 
LCM AGENDA
1. Introductory Comments – 5 minutes (RPM/Chairs)
Welcome, Introductions, Ground rules, Objectives of the Meeting 

2. Discussion of Substantive Review Issues – 60 minutes
a. Status of corrective actions to observations in Form FDA 483 identified during the inspection of --------(b)(4)--------------------------------- site.

b. In-support testing and overview of the August 6, 2014 Information Request (IR) regarding validation of analytical methods.

c. Status of responses to outstanding IRs for updated stability data and the Specification parameter ---------(b)(4)-----------------------.

3. Questions from Baxter – 10 minutes

4. Wrap up and Action Items – 10 minutes 

