
PSC Type C Meeting Questions, April 9, 2010 - Flublok


 
 

From: Fritz, Timothy

Sent:    Friday, April 09, 2010 4:40 PM

To:      Manon Cox

Cc:      Penny Post (penny.post@proteinsciences.com)

Subject:           CBER response to PSC Type C Meeting Questions for April 12 Face-to-Face Meeting

 

Importance:    High

 

Dear Dr. Post-

 

We have reviewed your March 15, 2010 pre-read materials for the April 12, 2010 meeting with CBER to discuss outstanding issues related to your FluBlok BLA 125285.

 

Protein Science Corporation’s questions are presented below followed by CBER responses in bold.

 

Thank you,

Timothy A. Fritz, Ph.D. Microbiologist FDA/CBER/OVRR/DVRPA/RRB2 WOC1 HFM-478 Suite 371N 1401 Rockville Pike Rockville, MD 20852 Phone: 301-827-3070 Fax: 301-827-1597

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General:

 

1.         PSC proposes to submit responses to individual CR letter items as they are completed, in a rolling format, in order to expedite the review process. We anticipate submissions to be made no more frequently than monthly. While we understand that the response will not be considered complete until the last item has been submitted, we envision that this mechanism facilitates a more rapid review. Would this be acceptable to the Agency?

 

CBER Response: CBER recommends that any submissions made in response to the January 11, 2010 CR letter in a rolling format contain a complete response to the CR letter item(s) addressed in the submission and that responses to individual CR items not be spread over multiple submissions. It would be helpful for PSC to provide CBER a timeline in advance for when complete responses for each CR item are expected.

 

2.         PSC’s objective is to complete its response to the CR letter by mid-June 2010, pending the Agency’s feedback during this meeting. Can the Agency clarify whether it will need the entire 6-month review timeline or whether review under a more accelerated timeline will be possible?

 

CBER Response: We cannot predict the time needed to review the Complete Response in advance of its submission. Upon receipt of a Complete Response, CBER will complete its review of submitted material as soon as possible within the time allowed under PDUFA guidelines.

 

3.         Does the Agency have additional comments or recommendations on the proposals and strategies presented in the meeting information package that are intended to address the outstanding CMC issues needed for licensure of FluBlok?

 

CBER Response: CBER does not agree with PSC’s decision to re-designate the rHA of the influenza B strain as B/Brisbane/33/08.  The strain designation provides important information regarding the derivation of the WVB and the passage history of the CDC reference strain from which the gene originated. Therefore, CBER recommends retaining the B/Brisbane/60/08 strain designation. Assuming the data PSC plans to provide demonstrates antigenic similarity to the reference strain B/Brisbane/60/08, there would be no cause for objection to your B rHA sequence. 

 

Process Validation (Item 1, 11 Jan 2010 CR Letter):

 

4.         FDA's January 11, 2010 CR letter comment 1a focuses on issues relating to the manufacture/purification of the HA from B/Brisbane/33/2008 (refer to footnote 1 on page 1 of this document). CBER's comment, however, references the final 2009 H3 Process Report (R-09-036). Can the Agency please clarify that comment 1a refers to the FluBlok Downstream Process Validation Report for rHA B strains, i.e., HA from B/Brisbane/33/2008 and not the H3 Process Validation Report (R-09-005)?

 

CBER Response: PSC is correct that comment 1a of the January 11, 2010 CR letter refers to the FluBlok Downstream Process Validation Report for rHA B strain and not the H3 strain.

 

5.         Background information regarding our plan to resolve the inconsistencies in yield and for rHA B strains (January 11, 2010 CR letter comment 1a) and the approved validation protocol are included in the Background Section of this meeting briefing document.

a.         Does FDA have comments regarding the protocol or specific comments on the submitted data or its interpretation?

 

CBER Response: The information provided in the briefing document should be included in your complete response together with CC-10-019 and any validation data (e.g., compatibility, extractable and potential leachables) to support the change. If not in the change control document, please also provide information that addresses changes in quality of rHA resulting from the change in –b(4)-------------------------------------------------------------------------------------------------. Stability results of the 3 validation lots should be provided.   Please provide similar information for other strains if this –b(4)------------------------- change will also be implemented for H1 and H3 purification.

 

Please note that a change control system should evaluate and approve proposed changes to specifications, test procedures, raw materials, facilities, support systems, equipment (including computer hardware), processing steps, packaging materials, and computer software. Changes could be categorized as minor or major depending on the nature and extent of the changes, and the effects these changes could impart on the process. In all cases, scientific judgment should determine what additional testing and validation studies are needed to justify a change in a validated process.

 

b.         Does successful execution of this protocol remove process consistency concerns for the B strains?

 

CBER Response: We agree.

 

c.         Can the agency please clarify the concern around -----b(4)------- for rHA B strains?

 

CBER Response: The –b(4)------- data previously provided for B validation lots has shown significant variability –b(4)-----Following the changes in –b(4)---------------------------- you have implemented, the         -----b(4)------ measured for the engineering run monovalent bulk appears to be acceptable. CBER’s concern regarding the –b(4)---------------- for PSC’s rHA B strains should be adequately addressed if –b(4)- similar to that measured for the engineering run are attained during the 2010 validation runs.

 

6.         Comment 1b of the January 11, 2010 CR letter is directed towards issues identified in the downstream processing of the manufacture of rHA derived from H1 A/Brisbane/59/2007. PSC has made improvements in –b(4)- column performance for the purification of the H1 rHA. The FDA VRBPAC recommended that A/California/07/2009 replace A/Brisbane/59/2007 as the recommended H1N1 vaccine strain. As a result, we propose to address this comment by re-validating the rHA H1 process using rHA derived from A/California/07/2009. A protocol similar to that for the B strain process validation (Attachment 1 of this document) will be used. Does the Agency concur that this is an acceptable approach? If not, what additional or replacement steps does CBER recommend?

 

CBER Response: Because data provided in PSC’s December 11, 2009 submission (including Reports 09-073 and 09-075) do not support consistent –b(4)- chromatography for purification of H1 hemagglutinin, we request a report of investigations that were done to identify the root cause(s) of discrepancies in b(4) column performance. This report should be completed prior to conducting the proposed H1N1 validation runs and should include:

 

·           An assessment of differences in elution profiles for 2009 H1 validation runs

·           A reassessment of investigation 09-073

·           A reassessment of the out-of-trend potency result for lot ----b(4)-----

·           The report should describe corrective actions that have been implemented to ensure consistent b(4) column performance. 

 

We concur with the plan to validate the H1 process using A/California/07/2009. If changes to the process were introduced, please include relevant data to support the change (process development data or change control documentation).

 

7.         PV2 (process validation run 2 for formulation and filling) has been filled at Hospira using rHAs derived from A/Brisbane/10/2007, A/Brisbane/59/2007, and B/Brisbane/33/2008. Data from PV2 will be included in our response to the CR letter. We are in the process of finalizing the fill date for PV3 at Hospira and we plan to complete this fill with rHAs derived from strains in compliance with those recommended for the 2010/2011 vaccine composition (A/California/07/2009, A/Perth/16/2009, B/Brisbane/33/2008). Data from this run will be submitted as soon as it becomes available. We plan to formulate PV3 using reagents from ---b(4)--- in lieu of having CBER H3/Perth SRID reagents. Is this an acceptable approach or does the Agency prefer that PSC waits until H3/Perth reagents will be available?

 

CBER Response: We agree with the use of the 2010/2011 formulation for PV3. CBER SRID reagents for A/Perth/16-like virus are scheduled to be available for distribution in mid-May. The CBER antigen for this reagent set is, in fact, made from the NYMC X-187 reassortant based upon A/Victoria/210/2009 as this is the dominant candidate strain for use in vaccine manufactured for distribution in the US. In this case CBER finds it acceptable, but not without risk, to use the b(4) reagent set for PSC’s H3/Perth-like strain until the CBER reagents become available. No manufactured lot will be released for distribution until b(4) and CBER reagents are shown to be equivalent and appropriate for testing PSC HAs.

 

Each fill run should be tested for stability. These results can be submitted as an amendment to the validation report but must be reviewed prior to product licensure. To maintain consistency, SRID potency reagents used to set formulation conditions should be used throughout the shelf life studies of any particular lot.

 

--b(4)----------- (Item 2, 11 Jan 2010 CR Letter):

 

8.         --b(4)----------------------------------------------------------  

 

--b(4)--  

 

--b(4)---  

 

--b(4)--- --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

 

a)         --b(4)---  

 

b)         --b(4)--- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

 

c)         --b(4)--- ---------------------------------------------------------------------------------------------------------------

 

--b(4)--  

 

d)         --b(4)--  

 

e)         --b(4)--  

 

b(4) Assays for Adventitious Agent Testing (Item 3, 11 Jan 2010 CR Letter):

 

9.         ----b(4) ?

 

--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------).

 

------(b)(4)------- (Item 4, 11 Jan 2010 CR Letter):

 

10.       Data generated to date to evaluate -----------(b)(4)------------- are provided in the meeting briefing package as well as the plans for further study. Does the Agency have any comments on this information or on the proposed additional studies?

 

--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------b(4)----------------------------------------------------------------------------------------------------------------------------------------?

 

---------------------------------------------------b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------b(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

 

--------------------------------------------------b(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

 

Product Purity (Item 7, 11 Jan 2010 CR Letter):

 

11.       Does the Agency have any comments on the product purity information submitted to the BLA on December 18, 2009 regarding purity assay validation, -b(4)--- testing to confirm removal by –b(4)--------, validation of Tween-20 assay, and –b(4)------------ DNA assay validation? Does this response adequately address CR Comment 7? If not, please specify the concerns.

 

CBER Response: PSC’s December 18, 2009 submission regarding purity assay validation, -b(4)---- testing to confirm removal by –b(4)--------, validation of the Tween-20 assay –b(4)----------- DNA assay validation is acceptable.

 

Outstanding Inspectional Issues (Item 8, 11 Jan 2010 CR Letter):

 

12.       PSC received feedback from CBER (teleconference of February 4, 2010 with Debbie Trout and Maryna Eichelberger) on the responses PSC submitted November 13, 2009, to the Form 483 received October 23, 2009, following the pre-licensure re-inspection of October 19-23, 2009. PSC anticipates submitting revised responses the week of March 15. Does FDA have any additional comments regarding inspectional observations and PSC’s responses to the October 2009 pre-licensing inspection?

 

CBER Response: We look forward to receipt of stability SOPs and your responses to observations 2, 4, and 7.