From: Ananyeva, Natalya 
Sent: Monday, May 12, 2014 5:16 PM 
To: 'Daizadeh, Iraj'; Lemieux, Linda 
Cc: Maruna, Thomas; Ananyeva, Natalya 
Subject: RE: BL STN: 125512/0: OBI-1 PAI Documentation Request from ----(b)(4)-------- 
---(b)(4)------ 
Importance: High
Dear Iraj and Linda,
During the course of the recent Pre-Approval Inspection at the ---(b)(4)---- site ----(b)(4- ------(b)(4)-------, it was agreed that Baxter will submit a number of additional documents, as an amendment to the BLA 125512/0, to address deficiencies identified during the inspectional interviews. To assist you in the preparation of the amendment, please refer to the discussion comments below:
1. During interview on critical steps and intermediates, it was noted that a number of hold times/process step times in the Drug Product manufacturing process are not supported in the BLA by actual study reports. These reports were provided for the inspector’s attention, and the Applicant committed to submit the following documents to the BLA file:
a. Sterile Filtration Validation Report PRV-RP-VSR(2)-002/113 to support the maximal allowable sterile filtration time of ---(b)(4)---.
b. Media Fill Study Report PRV-RP-PVR(1)-002/026 to support the maximal allowable filling time of ----(b)(4)---------.
c. Updated Stability Study Report SR128 to support the maximal allowable time from over-sealing to storage at refrigerated temperature of ---(b)(4)---.
d. Updated section 3.2.P.3.4 Controls of Critical Steps and Intermediates with any additional parameters, if controlled during routine manufacture, and with references to supporting documentation.
2. The test results in the Certificate of Analyses (CoA) for clinical, validation and subsequent batches of OBI-I presented during the inspection, although matched the results of Batch analyses in the BLA (section 3.2.P.5.4), did not match the data that were used to establish acceptance criteria for Drug Product Specifications (section 3.2.P.5.6 Justification of Specification). (b)(4)/Baxter explained that the difference was due to the change in the -----(b)(4)-------- criteria for ----(b)(4)-------------- methods and adjustment of Potency values for the current reference standard ---(b)(4)------- when moving from clinical to commercial material, that led to subsequent re-calculation of the data in CoAs. The Applicant committed to submit a supporting Document #112178- RPT/2.0 (which was provided for the inspector’s attention) to the BLA file. 
3. During interview on justification of Drug Product Specification, it was noted that the acceptance limit for ----------(b)(4)-------- is currently set based on the analysis of --------(b)(4)------------------ data which introduces a potential risk of not meeting Specification at the end of shelf-life. The Applicant acknowledged this potential risk and agreed to re-evaluate the acceptance limit using an alternative approach (e.g., separate analysis of release data and trend analysis of stability data), and inform FDA on the revised or verified acceptance limit.
4. The Applicant committed to submit up-to-date stability data for Drug Product (accumulated since submission of the BLA), based on Stability Study Report SR181. (b)(4)/Baxter also committed to include ---(b)(4)----- data for the Process Validation batches after data re-integration based on the criteria set for commercial product. (b)(4)/Baxter also committed to perform in-use stability study for the Process Validation batches at the latest stability testing time-point and include these new data in the Stability package.
5. Based on the discussion during the inspection, it was agreed that the following additional documents will be submitted to the BLA file:
a. Summary of Potency values for clinical, validation and subsequent Drug Product batches determined by One-Stage Clotting (OC) and Chromogenic Substrate (CS) assays with indication of assay reagents and standards that were used and the OC/CS ratio (response to Preliminary Record request #25).
b. Summary of comparative FVIII incremental recovery data determined by the OC and CS assays with the OC/CS ratio based on interim pharmacokinetic or clinical efficacy data (response to Preliminary Record request #27).
Please submit the available reports at your earliest convenience, and indicate the projected dates when responses to items 3 and 4 (requiring additional testing or data analysis) are expected to be completed.
Thank you.
Natalya
Natalya Ananyeva, Ph.D.
Senior Staff Fellow
LH/DH/OBRR/CBER/FDA
Phone: 301-827-6165
Natalya.Ananyeva@fda.hhs.gov 
From: Daizadeh, Iraj [mailto:iraj_daizadeh@baxter.com] 
Sent: Monday, May 12, 2014 9:07 AM 
To: Ananyeva, Natalya; Maruna, Thomas 
Cc: Lemieux, Linda 
Subject: BL STN: 125512/0: OBI-1 PAI Documentation Request from ---------(b)(4)---------------- 
(b)(4)--
Dear Dr. Ananyeva, and Lt. Maruna:
During the close-out meeting at the recent pre-approval inspection at the -----(b)(4)------- site (dated ----(b)(4)-------------, a request was made by Dr. Ananyeva to provide certain documents as an amendment to the BLA. Further, it was mentioned that the complete list of documents – including document numbers – would be forthcoming via email. If possible, Baxter would appreciate this document list in order to expedite processing of the amendment.
Thank you for your attention to this request, and please reconnect with any questions.
Best regards, Iraj
Iraj Daizadeh, PhD | Regulatory Affairs | work:+1-805-372-4934 | cell:+1-805-338-4882 | iraj_daizadeh@baxter.com
Mail Box Number: 1A-3, One Baxter Way, Westlake Village, CA 91362
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