Record of Telephone Conversation, October 8, 2013 - ALPROLIX

Submission Type: BLA    Submission ID: 125444/0    Office: OBRR
Product:          Coagulation Factor IX (Recombinant), Fc Fusion Protein
Applicant:       Biogen Idec Inc.
Telecon Date/Time: 08-Oct-2013 10:00 AM        Initiated by FDA? Yes
Communication Category:     1. Advice

Author: Edward Thompson
Revised:  Ellen Huang

Telecon Summary:     Discuss lyophilization (equipment qualification and technical runs) and container closure integrity testing

FDA Participants: 
John Eltermann, RPh, MS, Director, OCBQ/DMPQ
Jie He, MS, OCBQ/DMPQ
Ellen Huang, OCBQ/DMPQ
Marion Michaelis, Chief, Review Branch II,  OCBQ/DMPQ 
Laurie Norwood, Deputy Director, OCBQ/DMPQ
Destry Sillivan, MS, OCBQ/DMPQ
Edward Thompson, OBRR
Iliana Valencia, MS, Chief, RPM Branch, OBRR
Nancy Kirschbaum, PhD, Chemist, Division of Hematology, OBRR

Non-FDA Participants:
Biogen Idec
Amin Abujoub, VP, Global Quality Control
Eliana Clark, CMC Team Director
Tjebbe de Gruijter, Senior Manager, Contract Manufacturing
Olivia Henderson, Principal Scientist, Technical Development
Joseph Molon, Director, Analytical Technology
Sherry Tamura, Senior Manager, Analytical Technology
Clive Patience, VP Global Quality
Denise Schultz, Associate Director, CMC Regulatory Affairs
Suzanne Stella, Director, CMC Regulatory Affairs
Elijah Tan, Associate Director, CMC Regulatory Affairs
Andrew Weiskopf, Director, Technical Development
-(b)(4)-
--------------------(b)(4)-----------------------
--------------------------------------------------------------------
----------------------------------------------------------------------------------------

Telecon Body:
The facility reviewer requested this teleconference to discuss issues with Biogen Idec regarding lyophilization (equipment qualification and technical runs) and container closure integrity testing (CCIT).

Lyophilization

1.Regarding the vials for the drug product, FDA asked which vials will be using for the new Technical Runs. The firm indicated that they will be using the -(b)(4)- vials. The firm was asked which vials will be used for commercial purposes and the firm stated that they will be using ------------(b)(4)------------ vials. FDA mentioned that during a Type C meeting the firm had stated that these vials were equivalent. However, the firm has not yet provided data to show that the vials are truly equivalent. Previously FDA had requested the vial dimensions and the firm provided a minimum glass thickness for the bottom and a maximum bottom concavity and an approximate dimension for bottom/body radius. However, these are not actual specifications. Additionally, FDA noted that they found the CoA for the -(b)(4)- vials and it appeared to have minimum and maximum dimensions for the bottom of the vials. However, the CoA for the -(b)(4)- vials did not have dimensions. The firm was asked to provide the exact dimension specification requirements for the base of the vial (e.g. heel radius). FDA explained that differences in the vial, especially on the base, can impact the heat transfer and the lyophilization process. FDA communicated that if the firm is not able to provide data to show that the vials are equivalent with respect to lyophilization, the firm will need to use -----(b)(4)---- vials in their Technical Runs. Alternatively, the firm would be allowed to use only one of the vials upon approval of the BLA, though the other vial could be a post-approval supplement.


 

2.FDA communicated that once the equipment requalification is received, it will be reviewed, but since FDA did not get an opportunity to review the protocol, there may be additional comments/feedback. FDA expressed that their concerns were around the way the thermocouples (TCs) were placed; that is, they were not adhered to the shelf. It was also noted that there wide acceptance criteria for the shelf temperature was a concern.


 


Biogen indicated that the requalification has been performed last week at -(b)(4)-.  Biogen will provide a translated report to FDA by the end of next week. Biogen stated that they used -(b)(4)- methods in their requalification. ----------------(b)(4)------------------------------------------------------------------------------------------------. FDA indicated that additional information may be requested.

3.FDA noted that the firm will be using shelf (b)(4) for the minimum load Technical Run. FDA asked if that be the shelf used for the minimum loads during production. Biogen indicated that shelf ----(b)(4)--- shelf and will be used for the minimum loads for commercial use. FDA asked that -(b)(4)- procedures indicate that shelf (b)(4) should be used for minimum loads during routine production. Biogen agreed to submit this in writing.


 

4.FDA commented that the Biogen indicated that they removed the --------(b)(4)------------------ and that the (b)(4) does not need to be removed. FDA stated that (b)(4) can be used for collecting information. As stated previously, FDA communicated that the (b)(4) results cannot be used to drive the cycle time until they have validated that they can safely operate at the extremes of temperature and pressure that employment of a (b)(4) would engender (established correlation with the shelf temperature).



Biogen understood that this was for information purposes only. Biogen also thought that if the (b)(4) did not meet the requirements resulting in an altered cycle, that lot would be reported to the Agency for use.  FDA clarified that was not the case. If the firm wanted to use (b)(4), then validations should be performed and submitted as a supplement.

 

5.FDA asked what the acceptance criterion was for the product temperature mapping and asked the firm to ensure to include it as a requirement for the protocol acceptance criteria. Biogen agreed to the requirement. Biogen also asked what the criteria should be. FDA indicated that it should ensure show uniformity with the product loaded, be tight/close to the shelf temperature, and show correlation between the shelf and product temperature.


6.FDA requested that Biogen clarify that if during the product temperature mapping if samples taken from vials are filled with product. Biogen ------------(b)(4)----------------------------------------------------------------------------------.


7.FDA noted that the protocol stated that the -(b)(4)- IU drug product will be -(b)(4)-according to Table 2-1. The firm was asked to confirm if this is the same composition as your actual commercial product. Biogen stated that it is the same composition as their commercial product. FDA further asked the firm to explain why/how the drug product (DP) was being manufactured at ---------------------(b)(4)---------------------- explained since they needed a small amount of DP, they were ----(b)(4)---- the DP at their lab. Biogen restated that the DP will have the same composition and follow the same manufacturing steps.


 

8.FDA noted that the protocol stated that there may be abnormal vial vacuum levels and asked the firm to explain this. The firm explained that since the lyophilizer is opened -------(b)(4)-------- for sampling purposes, and this procedure does not represent their actual manufacturing process. Also, the vials will be -----(b)(4)----- capped.


9.FDA noted that the protocol for the maximum load on page 2 and 4 under section 2 and 3 only stated that the lyophilizer is filled with -(b)(4)-. However, the lyophilizer also will have -(b)(4)-. Biogen agreed to clarify the protocol indicating that the lyophilizer is filled ----------------------------------(b)(4)----------------------------------------------------.


10.FDA asked when the firm will be able to provide the data. Biogen stated they will provide the requalification reports by next week.  The minimum load technical run will be executed on October 10, 2013 and the final report will be completed November 14, 2013. The maximum load technical run will be executed on October 16, 2013 and the final report will be completed November 20, 2013. Both final reports will be submitted by November 20, 2013.


11.FDA also noted that in the future that they may want to discuss with the FDA prior to they perform lyophilization validation. FDA also communicated that the strategies that we discussed are not ideal and is not what we normally expect to see in a submission. Biogen agreed.


 

CCIT

1.FDA noted that the CCIT studies the firm provided employ a positive control of         -(b)(4)- for CCIT. The firm explained that -(b)(4)- performed studies to correlate the ---------(b)(4)---------- test (which they are using) to ---------(b)(4)------- CCIT. Their studies indicate that they are able to consistently/reliably detect a leak at (b)(4). FDA noted that (b)(4) is not consistent with current literature regarding the detection capabilities of the method. Furthermore, the average microbe is 4-6 µm, so if your limit of detection is around (b)(4) there is a reasonable chance that the test as performed cannot detect ingress of an average microbe. Biogen stated that they are using a -(b)(4)- test and was questioning FDA’s comments. FDA stated that since       -(b)(4)- was comparing the -(b)(4)- test with the ------(b)(4)------ test, FDA was stating the expectations for ----(b)(4)---- testing. The literature on this topic has generally reported that 10 µm is the general cut off point below which some test replicates in ----(b)(4)---- testing are not positive.  --------(b)(4)------ testing is generally reported greater sensitivity/lower limits of detection.  


2.FDA also noted that the positive control for ---(b)(4)--- test used for the stability testing of the DP (vials) was -(b)(4)-. The firm was asked why they are able to detect a leak at -(b)(4)- for stability testing of the vials versus the -(b)(4)- for qualifying the vials and syringes. Both methods are the ---(b)(4)--- test method. Biogen stated that the test methods are performed at different laboratories. FDA stated they understood this but it still does not address why the positive controls are different sizes.



Biogen stated they would provide a response regarding both of these concerns by October 15, 2013.

 

Other
FDA indicated that they will be sending additional information requests by the end of this week.
