Late-Cycle Meeting Summary
Application type and number:   STN BL 125512/0
Product name:   Antihemophilic Factor (Recombinant), Porcine Sequence
Applicant:   Baxter Healthcare Corporation
Meeting category:   Late-Cycle Meeting (LCM)
Meeting date & time:   August 19, 2014, 3:30 p.m. to 5:00 p.m. 
Meeting format:   Teleconference
Meeting Chair/Leader:   Natalya Ananyeva, PhD
Meeting Recorder:   Thomas J. Maruna, MSc, MLS(ASCP)
LCM package sent: August 7, 2014
FDA Participants: 
Natalya Ananyeva, PhD, Division of Hematology Research and Review, OBRR
Lokesh Bhattacharyya, PhD, Division of Biological Standards and Quality Control, OCBQ
Qiao Bobo, PhD, Division of Manufacturing and Product Quality, OCBQ
Nannette Cagungun, MS, PD, RAC, Office of Blood Research and Review
Dennis Cato, Division of Inspections and Surveillance, OCBQ
Wambui Chege, MD, Division of Epidemiology, OBE
Gilliam Conley, Director, Division of Inspections and Surveillance, OCBQ
Lisa Faulcon, MD, Division of Hematology Clinical Review, OBRR
Basil Golding, MD, Director, Division of Hematology Research and Review, OBRR
Nisha Jain, MD, Chief, Clinical Review Branch, Division of Hematology Clinical Review, OBRR
Alexey Khrenov, PhD, Division of Hematology Research and Review, OBRR
Tim Lee, PhD, Acting Chief, Laboratory of Hemostasis, Division of Hematology Research and Review, OBRR
Thomas Maruna, MSc, MLS(ASCP), Office of Blood Research and Review
Ginette Y. Michaud, MD, Deputy Director, Office of Blood Research and Review
Paul D. Mintz, MD, Director, Division of Hematology Clinical Review, OBRR
Loan Nguyen, Division of Case Management, OCBQ
Laurie Norwood, Deputy Director, Division of Manufacturing and Product Quality, OCBQ
Anne M. Pilaro, PhD, Division of Hematology Clinical Review, OBRR
Catherine Poole, MS, Regulatory Coordinator, Division of Biological Standards and Quality Control, OCBQ
Renee Rees, PhD, Division of Biostatistics, OBE
Destry Sillivan, Division of Manufacturing and Product Quality, OCBQ
Carl-Michael Staschen, MD, PhD, Division of Hematology Clinical Review, OBRR
Lisa Stockbridge, Division of Case Management, OCBQ
Tracy Tilghman, MPH, Office of Blood Research and Review
Boris Zaslavsky, PhD, DrSc, Division of Biostatistics, OBE 
Contractor Participant:
Christopher Sese, Independent Assessor, Eastern Research Group, Inc. 
Baxter Healthcare Corporation Attendees:
Mehrshid Alai-Safar, Sr. Director, Regulatory Affairs
Erik J. Bjornson, Director, Regulatory Affairs
Iraj Daizadeh, Senior Manager, Regulatory Affairs
Kien Du, Manager, Regulatory Affairs
Heinrich Farin , Associate Director, Clinical Research
Mathias Ferencic, Project Manager
Gabriele Gold, Manager II, Manufacturing Engineering
Mariah Hughlock, Regulatory Affairs Specialist
Doug Hunt, VP, Regulatory Affairs, Bioscience 
Linda Lemieux, Associated Director, Regulatory Affairs
Christoph Leonhart, VP, Quality
Jose Marques, Quality Control
Landon Piluso, Director, Analytical LCM
Susanne Schober-Bendixen, VP, Quality Compliance & Safety
Alexandra Schiviz, Senior Manager, R&D Pharmacology
Tatjana Surkova, Quality Operations
Harold Van Deinse, Senior Manager, Engineering, Validation
Donna Welch, Director Quality – FQMR
Peter Wojciechowski, Process Development
Background and Objectives:
The purpose of the meeting is to discuss substantive review issues and communicate our objectives for the review cycle of Biologics License Application (BLA), STN BL 125512/0, for Antihemophilic Factor (Recombinant), Porcine Sequence; Proprietary Name “OBIZUR.” The BLA was submitted to FDA in November 2013 under the PDUFA V Program for the proposed indication of the treatment and prevention of bleeding episodes in patients with acquired inhibitory antibodies to human Factor VIII (i.e., acquired Hemophilia A patients). This BLA has been reviewed under a Priority Review schedule with an original action date of July 26, 2014; a Major Amendment was received on April 25, 2014, extending the review clock to October 25, 2014. 
FDA sent the Late-Cycle Meeting package to Baxter Healthcare Corporation on August 7, 2014. 
Summary of the Teleconference:
The Regulatory Project Manager explained the purpose of the meeting and introduced the substantive review issues to be discussed at the meeting:
1. The status of the review of corrective actions to observations in Form FDA 483 identified during the inspection of Baxter’s -----------(b)(4)--------------------------- sites, presented by Dr. Qiao Bobo. 

2. Overview of the review of results of in-support testing and validation of analytical methods for the Drug Product, including the issues related to the August 6, 2014 Information Request, presented by Dr. Lokesh Bhattacharyya. 

3. Status of the review of responses to outstanding Information Requests for updated stability data and the Specification parameter -------------------(b)(4)-------------, presented by Dr. Natalya Ananyeva, Review Committee Chair.

4. Status of the clinical review, particularly with respect to the Final Clinical Study Report and supporting data submitted on August 8, 2014, presented by Dr. Lisa Faulcon. 
Facilities (Item 1) – Dr. Bobo:
Based on the information in Amendments dated June 27 and August 12, 2014, Baxter’s responses to Form FDA 483 issued during the pre-license inspection of Baxter’s (b)(4) facility are adequate. Baxter’s response (submitted on August 12, 2014) to Form FDA 483 issued during the pre-license inspection of ---(b)(4)-------- facility is under review. Regarding lyophilizer validation, FDA received the product temperature mapping data submitted on August 12, 2014. Baxter was asked to address the FDA comments provided during the August 14, 2014 teleconference, to include:
* Baxter’s assessment of the thermocouples that failed the post validation test to the validation including the locations of these thermocouples.
* A summary of the data for extended sampling testing (moisture content, reconstitution time, etc.) in relation to the locations of Baxter’s lyophilizer (---(b)(4)--- for maximum run and minimum run).
* Acceptance criterion for the secondary drying phase or provide a justification.
Additionally, Baxter was asked to provide:
* Summaries of available shipping validation activities and results (including simulated studies, shipping studies with worst-case final packaging configurations and shipping conditions, etc.) for shipping ----(b)(4)------------- from Baxter’s -(b)(4)- facility to ----(b)(4)------- facility, and the filled Drug Product from ----(b)(4)--------- facility to Baxter’s --(b)(4)- facility. Baxter was asked to follow up on February 14, 2014 Information Request Question 7 and Form FDA 483 Item #4.
* Clarification as to whether the Visual Inspection of lyophilized vials will be performed manually at Baxter’s ---(b)(4)-------- facility or semi-automatically at Baxter’s (b)(4) facility. Baxter was asked to follow up on February 14, 2014 Information Request Question 7. 
* Clarification as to whether Identity Testing of Drug Product is performed before and after labeling at the Baxter ----(b)(4)-----------------------------------------. Baxter was asked to clarify whether the Identity Test is validated and the same as submitted in the BLA, and whether the test is performed at the same location as the release testing. Baxter was asked to follow up on February 14, 2014 Information Request Question 8.
* Baxter was notified that if they decide to introduce other products into this facility after the licensure, an appropriate regulatory submission will be required.
Baxter agreed to submit all requested information by August 25, 2014. 
Baxter noted that this amendment will include the Shipping Qualification Report for the transport process of ---------(b)(4)-------------------- from the (b)(4) facility to the ---(b)(4)-- facility and the Interim Qualification Report for the transport process of Drug Product from the (b)(4)---- facility to the (b)(4)-- facility. The Final Shipping Validation Report (using commercial lots) will be available in March 2015, and Baxter is agreeable to submit it as a post-marketing commitment (PMC). FDA will determine the regulatory category for the Final Report based on the review of the Interim Report. 
In-Support Testing and Method Validation for Drug Product (Item 2) – Dr. Bhattacharyya:
In-support Testing 
Baxter was informed that FDA repeated their lot release tests for the Drug Product, which are considered critical, including potency assays by One-Stage Clotting and Chromogenic methods. With the exception of the Chromogenic assay, all other methods worked well – the results from the standards and/or controls met Baxter’s system suitability or assay validity criteria, and the results from the three lots of Drug Product tested were within Baxter’s proposed Specifications. 
FDA experienced problems with the Chromogenic assay. Baxter provided two different lots of the assay kit. The standard provided did not meet the acceptance criteria for R2 with one of the lots (kit ID (b)(4)). In addition, the results obtained using the two lots of the kit were different for three of the five lots tested. Furthermore, the information Baxter provided to FDA in the June 18, 2014 e-mail appears to contradict the information Baxter provided under “Justification of Specification(s)” in Amendment STN 125512/0.1. In the e-mail, Baxter directed FDA to use the potency data included in the e-mail, which match the data Baxter submitted to the BLA under “Batch Analysis.” However, under “Justification of Specification(s)”, Baxter provided different potency values for the same lots, which are approximately 13.5% lower, when ---(b)(4)---- is used as the reference standard. FDA requested clarification as to which of Baxter’s data sets should be used to compare with the FDA laboratory results, what standard Baxter used for testing Lots -----(b)(4)---------- (these two lots were not included in Baxter’s Justification of Specification(s) section), and whether re-calculation of potency values is necessary for them. FDA is unable to complete testing and draw conclusions in the absence of adequate clarification from Baxter. FDA suggested holding a teleconference to discuss this issue. 
Method Validation
FDA reviewed the methods and their validations for the quality control lot release tests for Baxter’s product and have outstanding issues with the validation of the Chromogenic potency assay. In the April 17, 2014 Information Request, FDA pointed out that Baxter used the same lot of the product both as the standard and the sample for the accuracy study, which is circular. While acknowledging that the approach is circular, Baxter provided additional data in which the same lot of the product was used as standard and sample for the accuracy study; this is still circular. In addition, Baxter performed the accuracy study in the range of (b)(4) of the target potency. FDA requested the accuracy data for the range of --(b)(4)-- of the target potency. FDA also requested adequate qualification data for the standard used in the method validation: in Baxter’s “Justification of Specification(s)” FDA noted significantly lower potency results when ---(b)(4)----- is used as the reference. These issues were communicated to Baxter in the August 6, 2014 Information Request. FDA requested a response from Baxter, including the data, by August 25, 2014 to be able to complete the review.
FDA stated that the information Baxter submitted in the August 13, 2014 Amendment has completely addressed the outstanding issues with the assays for sucrose, sodium and calcium. 
Baxter agreed to submit all requested information for the Chromogenic assay by August 25, 2014.
Outstanding Information Requests (Item 3) – Dr. Ananyeva:
FDA and Baxter/(b)(4) had previously discussed stability data for Drug Product (DP) and the identified deficiencies to support the proposed shelf-life and in-use stability of reconstituted DP (Question 4 in the May 12, 2014 Information Request, May 22 Amendment and Baxter’s commitment made during the June 9, 2014 teleconference). Baxter was asked to submit an update on sections 1 – 3 of Module 3.2.P.8 Stability, Drug Product, and related reports. Specifically, Baxter was asked to include (i) up-to-date stability data for all batches which are currently on stability testing, (ii) the re-integrated ---(b)(4)--- data for the Process Validation batches based on the criteria set for the commercial product, and (iii) the results of in-use stability study for the reconstituted product (Process Validation batches). 
FDA also requested that Baxter revise the Stability Program for Drug Product (Module 3.2.P.8.2) to include more frequent testing for Sterility and Endotoxin, specifically at 12 months, the end of the proposed shelf-life (24 months) and the end of the study ---(b)(4)--. Baxter was asked to include Container and Closure Integrity testing at all intermediate time-points. 
FDA and Baxter had previously discussed the acceptance limit for the Specification parameter ------(b)(4)-------------------------------------- which was set based on stability data and in a way that introduces a potential risk of not meeting Specification at the end of shelf-life. Baxter was asked to submit the results of the re-evaluation of the acceptance limit for (b)(4) using an alternative approach (e.g., separate analysis of release data and trend analysis of stability data) and to revise or verify the acceptance limit.
Baxter indicated that the Stability Protocol has been revised and will be submitted with the updated stability information by August 25, 2014. 
Baxter stated that the Specification for (b)(4) will remain unchanged (b)(4) but an additional limit, the Internal Upper Release Alert Limit (URL) for ---(b)(4)----------, will be implemented at the --(b)(4)--- site. FDA requested that Baxter provide justification for the URL and description of the actions to be taken when the limit is exceeded (i.e., the scope of investigation and Baxter’s strategy for batch disposition). Baxter agreed to include this information in the August 25, 2014 amendment. 
Clinical (Item 4) – Dr. Faulcon:
FDA received the Final Clinical Study Report (CSR) for Protocols OBI-1-301 and OBI-1-301a on August 8, 2014, with supporting data for the additional 11 subjects that were not included in the intermediate CSR. The review of the data is ongoing. 
Recommendations to the Prescribing Information and the vial and carton labels will be provided as part of the labeling review and will arrive within two weeks following the LCM.
Baxter acknowledged FDA’s comments.
Action Items:
1. Baxter will submit additional information regarding the lyophilizer validation requested by FDA at the August 14, 2014 teleconference by August 25, 2014.

2. Baxter will submit Shipping Qualification Report of OBI-1 -------------(b)(4)------------------------------------------------------------ by August 25, 2014.

3. FDA will review the Interim Qualification Report of the transport process from ---(b)(4)------------- facility to Baxter’s -(b)(4)- facility and will determine the regulatory pathway for the submission of the Final Shipping Validation Report using commercial lots based on the outcome of the review.

4. Baxter will submit information on the site and procedure of post-labeling Identity Test for Drug Product by August 25, 2014.

5. Baxter will submit responses to the August 6, 2014 Information Request related to the validation of the Chromogenic assay by August 25, 2014. FDA will set a teleconference to discuss the issue with in-support testing for August 22, 2014.

6. Baxter will submit a revised Stability Protocol and updated Stability data for Drug Product by August 25, 2014. Baxter will also provide justifications for the Internal Upper Release Alert Limit for (b)(4)-- and description of the actions to be taken when the limit is exceeded (i.e., the scope of investigation and batch disposition).

7. FDA will send Baxter recommendations to the Prescribing Information and the vial and carton labels within two weeks after the LCM.

8. Baxter will submit responses, organized by review discipline, in one amendment, and will refer to the original Information Request related to a specific issue.
Post-Meeting Comments
A teleconference was held on August 22, 2014 to discuss discrepancies between Baxter’s and FDA’s test results from the Chromogenic assay for potency. Baxter clarified that the potency values re-calculated to the use of the Primary Potency Reference Standard ---(b)(4)---- should be used for comparison with the results obtained by the DBSQC. Baxter acknowledged sensitivity of the Chromogenic assay to the assay kit and the standards used (International standards for FVIII concentrates or in-house recombinant porcine FVIII).
Considering that the Drug Product potency will be labeled with the One-Stage Clotting Assay (OSCA), FDA proposed and Baxter agreed to remove the Chromogenic assay (CS) as a Drug Product release assay for Potency and leave it “For-Information-Only.” Baxter will also remove the OSCA/CS ratio from Drug Product Specification. Baxter will include the formal request in the August 25, 2014 amendment.
