Information Request Email, August 22, 2013 - ALPROLIX	

From: Thompson, Edward
Sent: Thursday, August 22, 2013 9:07 AM
To: 'Nadine D. Cohen PhD (nadine.cohen@biogenidec.com)'
Cc: Kirschbaum, Nancy (Nancy.Kirschbaum@fda.hhs.gov); Huang, Ellen (CBER) (Ellen.Huang@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 the media fill for the drug product, there was an exception of the microbiological monitoring for media fill ----(b)(4)----. An objectionable organism (growth of spore forming germ) was found on a personnel. Please clarify if you have performed an investigation for the objectionable organism and a summary of your investigation.

2. Regarding the Bacterial Challenge Testing for the sterile filtration validation for the drug product:

a. Please clarify if it included the “worst-case” sterilization conditions. If not, please provide your rationale on why this is acceptable.

b. Please clarify if you have evaluated if the product is inhibitory or stimulator towards growth of --(b)(4)--. If so, please provide the results. If not, please provide a justification on why this is acceptable.

3. Regarding the hold time validations for the drug product, you only performed studies on two lots. For the diluent, you performed hold time studies on one lot. Please provide your rationale on why one or two lots are acceptable.

4. Please explain how the filled product is physically transported to the lyophilizer and how you prevent the contamination of the product during this process.

5. For the container closure integrity testing (CCIT) for stability testing of the drug product, please provide the pressure and vacuum cycle.

6. Please clarify why you used different test methods for CCIT during stability versus testing the initial container closure.

7. For all of your microbiological cycles in your sterilization validations please provide the BI locations (a graphical representation is acceptable) and your rationale on the placement.

8. Regarding ---(b)(4)--- sterilization

a. Please clarify which ---(b)(4)---- was used for the first summary (Document Number 5009120).

b. The second summary provided (Document Number 5009120) included a microbiological cycle. Please clarify what organism was used for this microbiological cycle, the population of the BI, and the D-value. Please clarify if there was any growth for the BIs placed in the load and if/what positive and negative control was used. Furthermore, it appeared that only four BIs were used. Please justify why this amount of BIs is sufficient.

c. In Document Numbers 5017449 and 5017450 you state that ---------(b)(4)---------- ------------------------------------------------------------------------------------ is the worst case material. Please provide justification why this is the worst case load and how it compares to the load of the subject diluent.

d. -(b)(4)- BIs were used in the requalification (Document Numbers 5017449 and 5017450). Please justify why this amount of BIs is sufficient.

9. Please clarify what distribution cycle and actual testing was performed for your shipping validations for the drug product and diluent. Please justify how the simulated testing conditions are worst-case compared to actual shipping conditions.

10. Please clarify if any new equipment were implemented as a result of the drug product or diluent.

11. Please provide how you ensure label reconciliation and accuracy of your labeling process.

12. Please clarify when and where identity testing of the drug product and diluent is performed.

13. Please provide a description of the vial, vial stopper, syringe barrel, -(b)(4)--------- system, and syringe plunger qualification program and the latest qualification results.

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 12, 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

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