Record of Telephone Conversation, August 20, 2013 - ALPROLIX


Submission Type: BLA    Submission ID: 125444/0    Office: OCBQ and OBRR
 Product:          Coagulation Factor IX (Recombinant), Fc Fusion Protein
 Applicant:       Biogen Idec Inc.
 Telecon Date/Time: 20-Aug-2013 11:30 AM        Initiated by FDA? Yes
 Communication Category:     1. Other – CMC/DMPQ Issues
 Telecon Summary:     Discuss drug substance/product lots, sterilization and lypholization process.
 FDA Participants: 
 Tim Lee, PhD, Acting Chief, CBER/OBRR/DH/LH
 Nancy Kirschbaum, PhD, CBER/OBRR/DH/LH
 Marion Michaelis, Chief, OCBQ/DMPQ/BII
 Destry Sillivan, Team Lead, OCBQ/DMPQ/BII
 Ellen Huang, Consumer Safety Officer, OCBQ/DMPQ
 Jie He, M.S., Consumer Safety Officer, OCBQ/DMPQ
 Edward Thompson, CBER/OBRR/RPMB

Non-FDA Participants: 
Biogen Idec Inc.
 Steve Doares, Associate Director, Manufacturing Sciences
 Tjebbe de Gruijter, Sr Manager Contract Manufacturing
 Brandon Laveille, Sr Engineer II, Technical Development
 Clive Patience, VP, Global Quality Assurance 
 Denise Schultz, Associate Director, Regulatory Affairs
 Suzanne Stella, Director, Regulatory Affairs

Telecon Body:

FDA initiated this teleconference to discuss the following questions:
1.Regarding lots -----------------(b)(4)---------------------- a.Which ------(b)(4)------- were these lots manufactured on?


The firm stated that they were manufactured on -(b)(4)-.
b.Were these lots manufactured before or after the DS conformance lots?


The firm stated that lot -----(b)(4)------ was manufactured -(b)(4)- days before the first conformance lot (lot -----(b)(4)------). Lot --------(b)(4)-------- was manufactured -(b)(4)- days after the last conformance lot (-------(b)(4)-------). The firm also stated that lot ------(b)(4)------- was manufactured under the process validation master plan. Biogen Idec was not sure if lot --------(b)(4)-------- was manufactured under the process validation master plan and they will confirm it. The firm also stated that none of the conformance lots will be released.

FDA communicated that if they were planning on releasing the conformance lots, DP lots containing DS lot ------(b)(4)------ may not have been able to be released since it was manufactured prior to the DS conformance lots. The firm stated they understood.

2.Please clarify if lot -(b)(4)- includes DS batch --------(b)(4)---------?


The firm confirmed that lot -(b)(4)- included DS batch --------(b)(4)--------.
3.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. 


The sponsor did not have -(b)(4)- on the call and thus were not able to answer this question. They stated they will communicate this to -(b)(4)- and have a response for us.
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 production 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.


The firm stated that they performed risk assessment to determine the worst case and will provide an explanation on how they determined the worst case goods.

4.Regarding lyophilization, please explain you approach to validating your lyophilized cycle to demonstrate batch to batch uniformity and consistency.


The firm referred to section 3.2.P.2 of the BLA. They stated they performed development work at the small scale and large scale. They referred to the technical runs and operating range study. FDA asked if the technical runs were run at the production lyophilization cycle. The firm stated that there were slight changes made during the technical run and that the final run was close to the final production cycle. The firm was asked to describe how the technical runs differed from the production cycle.

FDA also asked if they had a pressure driven cycle or a fixed cycle. The firm stated that the process validation runs were performed at a -(b)(4)- cycle.

FDA requested the firm to submit their complete validation of the lyophilization cycle and to be sure it includes sampling, an evaluation of the different vials and different fill volumes, and product data (e.g., potency, residual moisture, reconstitution time) across each shelf. The firm also clarified ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)------------------------ ).
5.Regarding the vials a.Please clarify if your product is stoppered under a vacuum.


The firm stated that their product is stoppered --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)--------------------------------------------------------------------------------------------------------------------------------------------. The firm was asked to provide that in writing.
b.Please provide a side-by-side comparison of the vials. Please include the base of the vial, heel radius, and thickness of the glass.


The firm said they would provide a comparison; however, they were not sure they had drawings of the base of the vial, heel radius, or thickness of the glass. FDA explained that differences between the two vial’s bases or wall thickness can change the thermodynamics for the lyophilization process.
c.Please clarify how each vial is manufactured.
 The firm stated they would get back to us on this.

d.Please provide the final release data for the -(b)(4)- vials. 
 The firm stated they would provide this data since it was not in the BLA. 
 The firm will provide written responses to these IR questions by September 5, 2013.
