Information Request Email, August 21, 2013 - ALPROLIX

From: Thompson, Edward
Sent: Wednesday, August 21, 2013 1:36 PM
To: 'Nadine D. Cohen PhD (nadine.cohen@biogenidec.com)'
Cc: Debra Segal; Huang, Ellen (CBER) (Ellen.Huang@fda.hhs.gov); Kirschbaum, Nancy (Nancy.Kirschbaum@fda.hhs.gov)
Subject: Information Request for BL 125444/0

Contacts: Nadine D. Cohen PhD

Dear Dr. Cohen:

We are reviewing your December 28, 2012 biologics license application (BLA) for Coagulation Factor IX (Recombinant), Fc Fusion Protein. We determined that the following information is necessary to continue our review:
1.Regarding lots -------(b)(4)------- and --------(b)(4)--------
a.Please clarify which ------(b)(4)------- were these were manufactured on.
b.Please clarify if these lots were manufactured before or after the date of manufacture of the DS conformance lots.
c.Please clarify if these lots were manufactured under the process validation master plan.
d.Please clarify if these lots were manufactured and tested exactly how the DS conformance lots were manufactured. If not, please provide the differences.
2.Regarding sterilization
a.In STN 125444/0/22, you mention that for the DP the “sterilization process the autoclave chamber can be equipped with -----------------(b)(4)------- carts onto which the goods are loaded according to defined fixed load patterns.” Please describe your --(b)(4)-- carts and clarify what you mean by defined fixed load patterns.
b.You also state that “the loads used for qualification/re-qualification purposes follow a ---(b)(4)--- concept in which all materials to be autoclaved are assessed and the worst case goods are identified. Based on this assessment the autoclave loads for qualification/re-qualification are defined to represent the worst case. This autoclave qualification and ---(b)(4)--- approach allows certain flexibility in routine productions cycles and has been validated by an initial validation using three individual validation runs.” Please clarify your ---(b)(4)--- approach and how you determine the worst case goods.
3.Regarding lyophilization
a.Please explain you approach to validating your lyophilized cycle to demonstrate batch to batch uniformity and consistency. Please clarify if you have performed empty chamber temperature mapping of each shelf to determine hot and cold spots of each, if any. Please provide a summary of those studies. Please also ensure you describe your sampling method (e.g. extended sampling, sampling pattern, which shelves sampled and sample locations, number of samples taken at each location), batch size of each run, fill volume of each run, product strength of each run, and testing results (e.g. residual moisture, potency, reconstitution time).
b.Please describe in detail how the technical runs differ from your actual production lyophilization cycle.
c.Please confirm that your lyophilization cycle is fixed.
d.Did you determine the ----(b)(4)-------- temperature of your product?
4.Regarding the vials
a.Please provide a side-by-side comparison of the vials. Please include specific dimensions of the base of the vial, heel radius, and thickness of the glass.
b.Please clarify how each vial is manufactured. 
c. Please provide the final release data for the -(b)(4)- vials.


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 response to this information request as an amendment to this file by September 5, 2013 referencing the date of this request. If you anticipate you will not be able to respond by this date, please contact the Agency immediately so a new response date can be identified.

The action due date for this file is December 28, 2013.

Please send an acknowledgement message for receipt of this request.

If you have any questions, please contact me at (301) 827-9167.

Sincerely,

Edward Thompson
 Regulatory Project Manager
 FDA/CBER/OBRR/DBA/RPMB
