Information Request Email, December 3, 2013 - ALPROLIX

From: Thompson, Edward
Sent: Tuesday, December 03, 2013 1:53 PM
To: 'Nadine D. Cohen PhD (nadine.cohen@biogenidec.com)'
Cc: 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.You stated in your protocols (in Amendment 45) that “some thermocouples may give inconsistent data during the lyophilization run and may not meet the above criteria.” Did any thermocouples give inconsistent data? If so, please provide that data and why it is acceptable.
2.Please provide the amended technical reports with corrected -----------(b)(4)------------ and ------------(b)(4)-------------.
3.In amendment 25, you stated that “lyophilization above the (b)(4) of the rFIXFc formulation may lead to -----(b)(4)----- behavior where the --------------(b)(4)--------------------------------------------------------------------------------- structure.” Please clarify at what point of the lyopholization cycle this may lead to -------------------(b)(4)-------------------------------------------------. In addition, please explain at what point of the cycle should the temperature be below ------(b)(4)----------.
4.Good lyophilization practice entails keeping the product temperature below the (b)(4) of the product during ----(b)(4)----. Please explain your rationale for your -----(b)(4)------ cycle being ----------(b)(4)-------------. Please provide your rationale why it is acceptable that the product temperature is -----(b)(4)----- during -----(b)(4)------. Please also provide the literature reference that supports your rationale.
5.Please explain why there is such a large difference in temperature between the ---(b)(4)-------------------------------------------------------------.
6.Historically, please clarify if you have observed any melt back. Please also provide how many lots were visually inspected.
7.Please clarify how many vials were sampled and tested for the process validation lots.
8.There appears to be a lag time between the --(b)(4) ----and (b)(4) vials. Please address how you have ensured that the (b)(4) vials have completed the ----(b)(4)-------- cycle at the end of the -----(b)(4)------.
9.Please provide the product temperature for each thermocouple at the end of each cycle. In addition, please provide the raw data for the last (b)(4) of the --------(b)(4)------- cycle for the fully loaded study (TR-PPD-005661).
10.Please clarify if the vials are placed directly on the lyophilizer shelf, on a tray or in/on a frame during the lyophilization cycle. Please explain what a frame is and how it is utilized for this process.

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 December 19, 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
