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Vaccines

Record of Telephone Conversation, May 4, 2012 - Flucelvax

 

Submission Type: BLA    Submission ID: 125408/0    Office: OVRR
Product:
Influenza Vaccine (MDCK Cells)
Applicant:
Novartis Vaccines and Diagnostics, Inc.
Telecon Date/Time: 04-May-2012 04:17 PM        Initiated by FDA? Yes
Telephone Number:
Communication Categorie(s):
1. Information Request
Author: TIMOTHY FRITZ
Telecon Summary:
SOPPs, validation reports
FDA Participants: Timothy Fritz
Non-FDA Participants: Matthew Gollwitzer
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
Telecon Body:
From:                    Fritz, Timothy
Sent:                      Friday, May 04, 2012 4:17 PM
To:                         'Gollwitzer, Matthew'
Subject:                 CBER Information Request for Optaflu BLA, STN 125408
 
Importance:           High
 
Attachments:         CBER Information Request 4 May 2012.doc
 
Dear Mr. Gollwitzer-
 
Our review of Novartis’ Optaflu BLA submission STN 125408 is ongoing. We have the following requests for additional information:
 
Polysorbate Assay for -------------(b)(4)----------------
 
1.     Please provide the following documents:
 
a.      The current version of SOP No. 105252.
b.     The version of SOP No. 105252 used in the validation performed in 2006.
c.      Analytical Test Method Validation Plan No. 233385.
d.     Technical report No. 234904.
e.      The Robustness Study Report, whether it was performed as part of method development, method validation, or independently.
 
2.     In addition to the information requested under 1 above, please provide the following information:
 
a.      A complete report of data analyses and calculations of Linearity, Range, Detection Limit, Quantitation Limit, if these analyses are not included in Technical report No. 234904.
b.     Justification for using only ----(b)(4)-------------- for method validation.
c.      The assessment report that should have been conducted in March 2008, as described in Document No. 235988 (Validation was performed in March 2006).
d.     The Revalidation Report that should have been conducted in March 2010, as described in Document No. 235988.
 
3.   Document No. 235988 stated the following acceptance criteria for the Specificity Study, “At retention times between -------------------(b)(4)----------------------------------------------------------------------------------- This by itself cannot be considered sufficient for demonstrating assay Specificity. Please provide an adequate Specificity Study.
 
4.   Document No. 235988 shows that an Interassay (i.e., Intermediate Precision as per ICH Q2(R1)) Study was performed by-----------------------(b)(4)---------------------------------. The study should also include results from ------------------------------------------------------(b)(4)----------------------------------------------------------, unless adequate justification is provided to do otherwise.
 
CTAB Assay for -------(b)(4)----------------------
 
5.     Please provide the following documents:
 
a.      The current version of SOP No. 104576.
b.     The version of SOP No. 104576 used in the validation performed in 2006.
c.      Analytical Test Method Validation Plan No. 233976.
d.     Technical report No. 234155.
e.      The Robustness Study Report, whether it was performed as part of method development, method validation, or independently.
 
6.     In addition to the information requested under 5 above, please provide the following information:
 
a.      The detailed calculations of the Correction Factor and justification for its use.
b.     A complete report of data analyses and calculations of Specificity, Linearity, Range, Detection Limit and Quantitation Limit if these analyses are not included in Technical report No. 234904. This may include the SAS output cited in Document No. 235978.
c.      Justification for using only ---(b)(4)------------ for method validation.
d.     The Assessment Report that should have been conducted in March 2008, as described in Document No. 235978 (Validation was performed in March 2006).
e.      The Revalidation Report that should have been conducted in March 2010, as described in Document No. 235978.
f.      The acceptance criterion for Interassay (i.e., Intermediate Precision as per ---(b)(4)-- Study was set as “relative standard deviation must not be higher than       (b)(4).” This seems to be very high for a chemical assay. Please provide a justification.
g.     Document No. 235978 includes the following statement:
 
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
 
--------------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------
 
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------
 
7.   Document No. 235988 shows that the Interassay Study was performed by -----------------------(b)(4)--------------------------------------. The study should also include results from ----------------------------------(b)(4)------------------------------------------------------------------------, unless adequate justification is provided to do otherwise.
 
Total Protein -------------------(b)(4)----------------------------------------------
 
8.   Please submit SOP 103347 or a full procedural description of the Determination of Total Protein by -----(b)(4)--------------. This should include a specific description of the protein standard used for control of accuracy as well as the working range of the procedure.
 
9.   Section 3.2.P.5.3.2.1 Validation of Analytical Procedures Total Protein Determination -------(b)(4)------------------ and linked Validation Report Doc. No 25879-02: 
  1. Validation characteristics do not include the defined range of this procedure. Please specify the procedural range as based on acceptable accuracy, linearity and precision.
  2. Precision is not addressed in the submitted report. It is stated in Section 4.3.1 that "Repeatability has already been calculated with different products listed in AVPP 254267 and does not need to be determined within this validation". An identical statement is made regarding Intermediate Precision in Section 4.3.2. Please submit the reports in which precision of this method as applied to the Optaflu ----(b)(4)------ has been evaluated. 
 
Test for Mycoplasma on Control Cells and Viral Harvests
 
10. As per 21 CFR 610.30 and FDA’s 2010 Guidance for Industry on “Characterization and Qualification of Cell Substrates and Other Biological Materials Used in the Production of Viral Vaccines for Infectious Disease Indications” production control cells and viral harvests must be tested for absence from Mycoplasma. We have following comments.
 
a.   You are not testing production control cells for Mycoplasma. Please include this test for the production control cells.
b.   For viral harvests, you are not performing the test for Mycoplasma by indicator cells method. Please include this method in testing viral harvests.
 
Test for Absence of Residual Infectious Virus
 
11. You have provided high level summaries of development and validation of the test for absence of residual infectious virus. For a complete review of this method, please provide the following documents and information.
 
a.      In Document No. 231299, Section 5.1, data presented indicate that all 3 strains of the control virus preparation were detected at ---(b)(4)------.  In section 4.3, the document states that “lower dilutions may still be completely or partially positive, since a tailing effect is to be expected.”  Please explain the tailing effect leading to detection of -------(b)(4)----- of experiments for all 3 strains.
b.     In Document No. 231299, Section 6, you mentioned that the detection limit of the  --(b)(4)---- method was compared with that of the ---(b)(4)--------- method.  Please indicate if the amount of the virus inoculum in the two methods was the same for the two methods for a meaningful comparison.
c.      Test method SOP 105243 for testing residual infectious virus by ---(b)(4)----.
d.     EDMS document No. 231855, describing study to determine detection limit of  ---(b)(4)------- method in different ----(b)(4)------ preparations containing HA.
e.      Analytical Test Method Validation Report 403031 for evaluation of detection limit in ----(b)(4)------- for the 3 test virus strains.
 
CMC
 
12. Please justify the changes to FCC process 1.1 by providing supportive data including, but not limited to, impurity profiles, the -----------(b)(4)----------------------- identification and ----(b)(4)-------------- results to demonstrate the comparability of  ---(b)(4)--------- manufactured by FCC process 1.0 and 1.1.
 
11. Please provide the following validation reports for the homogeneity of hemagglutinin and ------(b)(4)------------: AVP 233393 and AVR235802 referred to in 3.2.S.4.3.7 and attachment 3.2.R.3-235802, respectively.
 
12. On p. 46 of 3.2.A.2 (Adventitious Agents Safety Evaluation), Attachment 3.2.A.2.5.2.2-1, a summary of BPL inactivation studies for model viruses is provided. However this Attachment only describes inactivation by BPL of ---(b)(4)--------. Please submit the correct referenced general summary of the BPL inactivation studies.
 
13. Table 3.2.A.2.5.2.2-1 and Table 3.2.A.2.5.2.2-2 of 3.2.A.2 (Adventitious Agents Safety Evaluation) provide an overview of the BPL inactivation results. Please provide the study reports for viruses capable of replicating in MDCK cells: ---(b)(4)-------- -(Study No. AS 02/00-18), ------(b)(4)---------------------- (Study No. AS 03/02-52 and Study No. AS 10/02-58), -------(b)(4)-------------------- (Study No. 02/02-50).
 
14. The revalidation data for the removal of BPL in ----(b)(4)------- manufactured by process 1.1 will not be available until the end of August.  In the meantime, please provide the residual BPL content of the most recently manufactured ---(b)(4)------- lots and the validation of the assay used for the determination of residual BPL.
 
15. We understand that the completion of the validation of the (b)(4) purification columns depends on the production schedule, and the final report will not be available until December -(b)(4)-.  With the lack of column lifetime validation data, you need to closely monitor the performance of the columns based on the quality of the intermediate product and the periodic column suitability test through (b)(4) runs.  If there are any signs of deteriorating performance of the columns, you have to reduce the shelf life accordingly.
 
Please submit the requested information as an amendment to STN 125408. We recommend that you restate each item and follow it with your explanation or clarification. Use of this format helps organize the relevant information and provides a self-contained document that facilitates future reference.
 
If you have any questions, please contact the Regulatory Project Manager, Drs Brenda Baldwin or Timothy Fritz, at 301-796-2640 or via e-mail.
 
Thank you.
Timothy A. Fritz, Ph.D.
Microbiologist
FDA/CBER/OVRR/DVRPA/CMC2
WOC2 HFM-478
1451 Rockville Pike
Rockville, MD 20852
Phone: 301-796-2640
Fax: 301-827-1597
 
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