Record of Telephone Conversation, September 16, 2013 

Submission Type: BLA    Submission ID: 125444/0    Office: OCBQ 
Product:          Coagulation Factor IX (Recombinant), Fc Fusion Protein
Applicant:       Biogen Idec Inc.
Telecon Date/Time: 16-Sep-2013 10:00 AM        Initiated by FDA? Yes
Communication Category:     1. Other – DMPQ Issues
Telecon Summary:     Discuss lyophilization and sterilization.
Telephone: -----------------(b)(4)------------------
FDA Participants: 
Jay Eltermann, Division Director, OCBQ/DMPQ
Destry Sillivan, Team Lead, OCBQ/DMPQ/BII
Ellen Huang, Consumer Safety Officer, OCBQ/DMPQ/BII
Jie He, M.S., Consumer Safety Officer, OCBQ/DMPQ/BII

Non-FDA Participants: 
Biogen Idec Attendees:
Jessica Ballinger, Senior Director, Technical Development 
Eliana Clark, CMC Team Director 
Tjebbe de Gruijter, Senior Manager, Contract Manufacturing
Kim Hocknell, Director, CMC Team Director, rFIXFc
Brandon Laveille, Senior Engineer, Technical Development
Rohin Mhatre, VP, Technical Development 
Clive Patience, VP Global Quality 
Tarita Qveflander, Manager, Manufacturing Science 
Denise Schultz, Associate Director, CMC Regulatory Affairs 
Suzanne Stella, Director, CMC Regulatory Affairs

-------(b)(4)—Attendees:
------------------------------------------------------------------------
-------------------------------------------------------------------------
----------------------------------------------------------------
------------------------------------------------
-------------------------------------------------------------------
-------------------------------------------------
---------------------------------------------------- 

Telecon Body:

FDA initiated this teleconference to discuss lyophilization and sterilization:
1.Lyophilization

FDA discussed the expectations for the lyophilization qualification and validation of the lyophilization cycle. They explained that these studies should include empty chamber shelf temperature mapping, full scale product temperature mapping, and extended sampling of the maximum and minimum lyophilization loads.

The Agency asked if any extended sampling was performed during the process validation (PV) and the firm stated that they had not performed any such extended sampling. The firm explained that random samples were selected from the PV lots and placed on stability and that since the PV lots were intended for human use, they did not perform extended sampling. They did not want to place thermocouples (TCs) in product during the PV lots. FDA explained that they understand not wanting to place TCs in the PV lots and that extended sampling does not need to include temperature probed products. Extended sampling is samples taken from predefined locations in the lyophilizer and tested for product attributes. Typically, samples are taken in a -------------------(b)(4)------------------------ and other random locations for each shelf. This data is used to support batch to batch uniformity and consistency.

The firm also stated that the Technical Runs included extended sampling and represented the full scale. DMPQ explained that the Technical Runs were not sufficient since the lyophilization cycle did not reflect the final production cycle. For example, Technical Run 1 was (b)(4) hours shorter than the actual production cycle       (------------------------------(b)(4)--------------------------------). All the other technical runs were (b)(4) hours shorter than the actual production cycle. Additionally, extended sampling was not performed on those cycles. The Technical Runs did not include every shelf and samples were not taken from a --(b)(4)--. Furthermore, there was a large variation observed in the temperature mapping, which leads to concern about the control over the lyophilization process. For example, some runs where the product temperature had (b)(4) of difference within a shelf (Technical Run 3). Additionally, the lyophilization load size for Technical Run 2 did not represent actual production load sizes. Technical Run 2 only included a ---(b)(4)--- vials when the minimum load size is (b)(4) vials.

Next, DMPQ discussed the empty chamber shelf temperature mapping study. The information request stated that they have demonstrated (b)(4) temperature control across the (b)(4) shelves over the range of ---(b)(4)----. The Agency stated that there should be limited variability during the temperature mapping study. However, it was not clear what the actual temperature variation was for each shelf and from shelf-to-shelf. Additionally, the maximum deviation from the ---(b)(4)--- the sensors acceptance criteria was ----(b)(4)----, and it is unclear why they would allow such a large variation in the lyophilizer. Furthermore, only the ----(b)(4)------- set points were evaluated. The actual shelf temperatures for the final production cycle are --------------(b)(4)----------------. The empty chamber study should evaluate additional set point temperatures used for the actual production cycle. In addition, only (b)(4) out of the (b)(4) shelves were mapped and only (b)(4) TCs were used. Again, a --(b)(4)-- is typically used on each shelf. If a --(b)(4)-- was used, (b)(4) TCs should have been employed.

-(b)(4)- stated that they have been using --------------(b)(4)--------” lyophilizers and their lyophilizers are robust equipment. The shelves -----------------(b)(4)--------------------------------------------------------------------------------------- also stated that they have performed initial qualification of their lyophilizer, which included (b)(4) TCs (b)(4)----- ((b)(4) TCs total). However, during their requalification, they -(b)(4)-- the number of TCs to (b)(4). They placed --(b)(4)---------------------------------------------------------------------------------------------------------------------------------. DMPQ asked for the initial empty chamber temperature mapping study.

DMPQ stated that industry standard is ±2°C variation in shelf temperature and asked the firm why they allow ---(b)(4)--- stated that the -(b)(4)- acceptance criterion is the variation allowed from the set point of the shelf. The Agency asked what they are using to drive their cycle (e.g. pressure driven cycle or set point driven). The firm stated that ---------(b)(4)---------- drives their cycle. DMPQ brought up during their last telecon on 8/20/2013 that they stated that they have a -(b)(4)- cycle. The firm clarified that they have a -(b)(4)- cycle and that at the end of ----------(b)(4)---------- ---------- they perform a --------------(b)(4)-------------. If the -(b)(4)- does not meet the acceptance criteria, they will prolong their cycle. The firm pointed out that the operating range study at the low end --------(b)(4)--------- extended the cycle by (b)(4) hours and can be used to support the prolonged cycle. FDA stated additional data would be required to support a ---------------(b)(4)----------------- cycle. DMPQ explained that if they plan on using a ------(b)(4)------ cycle, which essentially utilizes a ----(b)(4)----- concept, extensive data is need to support each extreme. DMPQ recommended that they use a -(b)(4)- to drive their cycle and use the (b)(4) for information use only. If the firm wanted to use a -----(b)(4)----- cycle, they can summit it in the future as a supplement to the approved BLA. The firm then stated that they are only going to run at the target -(b)(4)- and they are not utilizing the results of the -(b)(4)- to determine ---(b)(4)----endpoints.

The firm asked what they needed to do to provide the data we needed. The Agency requested the following items.
a.Empty chamber shelf temperature mapping study
b.Product temperature mapping study at full scale (can be done with --------(b)(4)---- with product)
c.Extended sampling with actual product (testing can include items such as moisture mapping, reconstitution time, and/or potency) of the maximum and minimum load.

After explaining the data FDA was looking for, the firm stated that their Technical Runs and Operating Range Studies provide us the data we need. They stated that the Technical Runs represented the maximum and minimum loads. DMPQ explained that the Technical Runs were development work and cannot be used to substitute for the validation of the final lyophilization cycle. Additionally, the Technical Runs did not represent the final cycle and there was a large variation seen in the lyophilizer.

The firm asked again what they need to provide to us. The Agency explained that the data provided is not robust and extended sampling was not taken. DMPQ explained there is no assurance that their final cycle is capable of manufacturing batch to batch uniformly. Additionally, the firm has not showed they can correlate pressure with temperature performance. FDA stated that can demonstrate this correlation during the requalification of the lyophilizer and can be performed with –(b)(4)----. The Agency again repeated the requested item FDA wanted (empty chamber shelf temperature mapping, full scale product temperature mapping, and extended sampling).

The firm asked us to explain what we mean by extended sampling. FDA explained that it is pre-defined locations that are sampled and tested for product attributes. The Agency also explained that samples should be taken in ----(b)(4)-----and random other sample locations from all shelves.

The firm also asked if this information could be provided as a post marketing commitment (PMC). FDA stated that this cannot be a PMC and is needed prior to approval.

The Agency asked the firm to summarize their understanding of FDA’s concerns and their plan to correct it. The firm agreed to this.
2.Sterilization

FDA asked to firm to confirm that no new sterilization validations were performed on their new equipment for rFIXFc. -(b)(4)- confirmed that there is new equipment for rFIXFc and no new sterilization validations were performed for the new equipment.    -(b)(4)- stated that they performed an assessment to determine if the new equipment was a new “critical item” (i.e. worst case). If it was not a critical item, a new validation was not required. If the new equipment is a critical item, then the sterilization cycle is validated. No new equipment for rFIXFc was considered a new critical item.

The risk assessment considered items such as material of ------------------------------------------------------------------------------------------------------------------(b)(4)--------------------------------------------------------------------).

FDA asked if their assessment consider items such as --------------------------------------------------------(b)(4)--------------------------------------, etc. The firm stated that all of those items were considered under “-------------(b)(4)-----.” FDA stated they had no further questions regarding sterilization at this time.

The call ended at 11:16 AM.

