Record of Telephone Conversation, December 2, 2013 - ALPROLIX

RECORD OF TELEPHONE CONVERSATION
 Submission Type: BLA    Submission ID: 125444/0    Office: OBRR
 Product:          Coagulation Factor IX (Recombinant), Fc Fusion Protein
 Applicant:       Biogen Idec Inc.
 Telecon Date/Time:   02-Dec-2013 10:00 AM        Initiated by FDA? Yes
 Communication Category:     1. Other - Lyophilization Process

Drafted:    Edward Thompson
 Revised:    Ellen Huang

Telecon Summary:     To discuss questions from DMPQ for the lyophilization process

FDA Participants: 
 Marion Michaelis, Chief, OCBQ/DMPQ/BII
 Ellen Huang, OCBQ/DMPQ/BII
 Jie He, MS, OCBQ/DMPQ/BII
 Nancy Kirschbaum, PhD, OBRR/DH/LH
 Edward Thompson, OBRR

Non-FDA Participants: 
Biogen Idec
 John Cox, Executive Vice President, Pharmaceutical Operations & Technology
 Alasdair Shepherd, VP, Quality, Swiss HQ (USD) Supply Chain Quality
 Suzanne Stella, Director, Regulatory Affairs
 Mariana Dimitrova, Director Technical Development, MA Protein Formulation Development
 Eliana Clark, CMC Team Director
 Kevin Maloney, Associate Director, Technical Development, Therapeutics Protein Formulation Development
 Denise Schultz, Associate Director, Regulatory Affairs
 Tjebbe de Gruijter, Sr Manager, Contract Manufacturing

------(b)(4)---Attendees
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Telecon Body:
 The following items were discussed with Biogen Idec from the DMPQ facility reviewer for this application. Questions that were asked by the FDA are italicized and the discussion with the firm is in regular text.
1.You stated in your protocols that “some thermocouples may give inconsistent data during the lyophilization run and may not meet the above criteria. The product quality from these locations will be tested to check if the product quality is still acceptable.” Did any TC give inconsistent data? 

Biogen stated all TC gave consistent data.
2.Please clarify if Table 7-2 in the reports is for the whole hold time or only at the end of the hold time. 

Biogen responded with only at the end of the hold time.
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)----------------------------------------------------------------------------------.” Can you please clarify at what part of the process should the lyophilization --------(b)(4)-------------of the rFIXFc formulation may lead to ----(b)(4)---- behavior? 

Biogen said the --(b)(4)-- step manages the --(b)(4)--. Biogen explained that the          ----------------------------------(b)(4)----------------------------------------------------------. During ------(b)(4)-------, the temperature should be ------------------(b)(4)-------------------------------. During --(b)(4)--, the temperature should be --------------(b)(4)---------------------------.
4.In your reports, you stated that the ---(b)(4)---. Please clarify this discrepancy. 

Biogen stated that there was an error in the reports provided. The actual ---(b)(4)---. The firm stated that section 7.1 of the report should have actually stated that “during the ----(b)(4)--------- portion of the cycle, all of the vials were maintained --(b)(4)-- product ------------(b)(4)----------------------------------(b)(4)--------------------- until        –(b)(4)--- was completed…” Biogen stated that would provide the amended reports with the corrected information.

5.Please explain why there is such a large difference in temperature between the -------(b)(4)------ temperature and --(b)(4)-- temperature. 

Biogen said the ------(b)(4)---------------- and therefore there is a difference between the ----------------------------(b)(4)------------------------------. The --(b)(4)-- temperature was measured by -------------(b)(4)------------- and determined to be (b)(4) for the 3000 IU. The firm noted that the -------(b)(4)--------.

FDA noted that the acceptance criteria was less than or equal to (b)(4) for the             --(b)(4)-- process and asked if the --(b)(4)-- process should be ----(b)(4)----, why is the acceptance criterion for the product temperature allowed to be (b)(4). Biogen explained that the actual results worst case results was (b)(4).

Biogen also explained that (b)(4) is important for the -----------------(b)(4)----------------. Biogen committed to provide literature references for lyophilization of --(b)(4)--structures. 
6.Regarding your acceptance criteria for the temperature mapping: a.Please note that you have set very large ranges for your acceptance criteria. Additionally, your acceptance criteria are set close to the limits (e.g. freezing must be --(b)(4)-- and the acceptance criteria is --(b)(4)--). There is variability in the shelf temperature ((b)(4)) and in the thermocouples. We recommend that you don’t set your acceptance criteria so close to the limit.


Biogen acknowledged FDA’s comment.
b.Since you stated that it’s important that---(b)(4)------------------, why wasn’t that part of your acceptance criterion? 

 Biogen explained that according to the paper by ----------------(b)(4)------------------------------------------------------------------------------------------. It can be seen in the temperature traces that the product temperature was --(b)(4)-- prior to -(b)(4)------.
c.Please explain your rationale for your acceptance criterion for -------(b)(4)-------.

 Biogen stated that the (b)(4) was based on actual data and the (b)(4) was based on the ----(b)(4)---- of the lyophilized product ((b)(4)). Biogen referred to Amendment 25, which states that the (b)(4) for the (b)(4) IU and 3000 IU were --(b)(4)--, respectively.

4.Good lyophilization practice entails keeping the product temperature ----(b)(4)-------- of the product during ----(b)(4)------. Please explain why it is acceptable that the product temperature is ----(b)(4)-----. 

Biogen stated that they observe ------(b)(4)----------- so they wanted to maintain the drug product below that. Biogen also stated that sometimes the -----(b)(4)------------------- is hard to measure for ---(b)(4)--- product. Biogen said that at the end of ---(b)(4)--- step the -------------------------------(b)(4)--------------------------------.

FDA requested the literature for (b)(4) temperature and Biogen agreed to provide it.
7.Please provide the raw data for each run.

Biogen agreed to submit the tables for every thermocouple at the end of hold time.
8.Please clarify if you have observed any melt back. 

Biogen stated they 100% inspect their vials and did not observe any melt back.
9.Please provide how many samples were taken for the process validation lots.

 Biogen agreed to provide this information.

Biogen agreed to provide the requested information in two weeks.
