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Vaccines, Blood & Biologics

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Vaccines

Record of Telephone Conversation, June 6, 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: 06-Jun-2012 04:29 PM        Initiated by FDA? Yes
Telephone Number:
Communication Categorie(s):
1. Advice
 
Author: BRENDA BALDWIN
Telecon Summary:
Partial response to 5-25-12 e-mail from Novartis
FDA Participants: Brenda Baldwin, Timothy Fritz
Non-FDA Participants: Matthew Gollwitzer
Trans-BLA Group: No
 
Related STNs: None
Related PMCs: None
E-mail Body:
 
Sent:Wednesday, June 06, 2012 4:29 PM
To:Gollwitzer, Matthew
Cc:Fritz, Timothy
Subject:BLA 125408 partial response to 5-25-12 e-mail
Sensitivity:Confidential
 
Dear Brenda,
 
As Novartis Vaccines and Diagnostics (NVD) plans to begin manufacture of the Optaflu commercial batches in June for the 2012 flu season, we would like to engage Dr. Gupta as soon as possible. Outlined below is a list of questions for Dr. Gupta.   NVD would like to set up a teleconference with Dr. Gupta to discuss and seek advice on the following questions and therefore would like to know if it is acceptable to reach him directly.
 
1.  Does CBER have any comments or questions to the following:
 
  • As part of Optaflu BLA review, NVD shipped monobulk samples for testing. Are there any follow-up questions for NVD based on testing of these samples?
  • Report (titled, Qualification Report for suitability of CBER egg-based influenza reference reagents for use with the flu cell culture generated material for testing of HA potency) submitted in Amendment 0008 demonstrating suitability of use of the egg based reagents for SRD testing
  • On the report submitted in Amendment 0008 (titled, Summary Report for the Verification of the Method SOP 269284: Determination of Hemagglutinin Content by SRD (USA), for Testing FCC ----(b)(4)---- Samples)- US SRID parallel line method
 
2.  Does CBER have any comments on the lot release protocol (LRP) submitted to CBER in Amendment 0008? If CBER does not have any comments at this time, when can NVD expect comments from CBER?
 
As communicated in Amendment 0008, NVD incorporated Dr. Gupta’s guidance on the requirements for LRP based on Agriflu (as discussed in the teleconference on March 7th). NVD wishes to confirm that the level of detail to be reported for those tests is acceptable and seeks to finalize the LRP.
 
3.  As discussed in the March 07 teleconference with CBER, Dr. Gupta made a recommendation to re-classify the trivalent bulk as sterile. Furthermore, it was Dr. Gupta’s expectation that NVD would ship sterile trivalent bulk with 2012 strains. Considering the start of commercial manufacture in June 2012, NVD will not be able to meet the timelines for sterility and requests either to waive such requirement based on recent CFR amendment or incorporate this method post-licensure starting from 2013 flu season. Does CBER find this acceptable?
 
A further discussion around this topic can be found in Attachment 1 (end of document).
 
4.  NVD intends to ship 2012 strain monobulk samples and trivalent bulk samples to CBER for testing and development of CBER standards for release. NVD also intends to ship seed virus as part of the annual strains change procedure. What is CBER’s expectation in terms of timing for receipt of these samples, the number of lots required, and the volume of samples?
 
 
5.  NVD would like to submit an annual update for 2012 season flu strains. This could be submitted by July-Aug timeframe prelicensure and/or post-licensure in Oct for expedited approval. NVD is seeking advice on CBER expectations for submission timing for the annual update.
 
 
Please let me know at your earliest convenience.
 
Thank you and kind regards,
 
Matt
 
 

 
Hi Matt,
 
We have the following responses to questions 1 and 4 from your e-mail dated May 25, 2012:
 
1.   Does CBER have any comments or questions to the following:
 
  • As part of Optaflu BLA review, NVD shipped monobulk samples for testing. Are there any follow-up questions for NVD based on testing of these samples?  We are providing the results of the monovalent testing. Please note that the HA content measured by SRID in the CBER lab is lower than the results provided by NVD. These differences are greater than 20% for 3 lots of A/Brisbane/59, 4 lots of A/Victoria/210 and 1 lot of B/Brisbane/60. CBER and NVD will need to come to an understanding on the cause for these differences greater than 20% in the SRID results.  If the root cause for such differences cannot be determined, NVD has to assure that final formulated vaccine passes the SRID test at CBER during lot release.
  • Report (titled, Qualification Report for suitability of CBER egg-based influenza reference reagents for use with the flu cell culture generated material for testing of HA potency) submitted in Amendment 0008 demonstrating suitability of use of the egg based reagents for SRD testing We note that some of the lots that were received for testing were also used in the qualification study; however, the SRID results for most of those lots reported in the qualification report are different than what were provided to CBER in the e-mail dated April 19, 2012
  • On the report submitted in Amendment 0008 (titled, Summary Report for the Verification of the Method SOP 269284: Determination of Hemagglutinin Content by SRD (USA), for Testing FCC ----(b)(4)----  Samples)- US SRID parallel line method No comment at this time.
 
4.   NVD intends to ship 2012 strain monobulk samples and trivalent bulk samples to CBER for testing and development of CBER standards for release. NVD also intends to ship seed virus as part of the annual strains change procedure. What is CBER’s expectation in terms of timing for receipt of these samples, the number of lots required, and the volume of samples? Please clarify your question regarding bulk samples and development of CBER standards for release. Regarding the seed virus, we recommend that 3-5 vials (1ml/vial) of each seed lot be sent to DVP in CBER for the antigenicity/ID test. The seed viruses can be submitted to CBER anytime for ID testing.
 
We should be able to provide the response to questions 2, 3 and 5 in the next few weeks. Regards,
Brenda
 
 
 
Sent:Monday, June 18, 2012 1:03 PM
To:Baldwin, Brenda
Cc:Fritz, Timothy
Subject:RE: BLA 125408 partial response to 5-25-12 e-mail
Sensitivity:Confidential
 
Hi Brenda and Tim,
 
Regarding question # 4, we would like to clarify the question.
 
NVD intends to ship 2012 strain monobulk samples and trivalent bulk samples to CBER for concurrent testing. What is CBER’s expectation in terms of timing for receipt of samples, the number of lots required, and the volume of samples?
 
Please let me know if this clarifies things. Kind Regards,
Matt

 
From:Baldwin, Brenda
Sent:Tuesday, June 19, 2012 2:58 PM
To:'Gollwitzer, Matthew'
Cc:Fritz, Timothy
Subject:RE: BLA 125408 partial response to 5-25-12 e-mail
Sensitivity:Confidential
 
Hi Matt,
 
You can send the samples when they are ready. Please notify us when you are ready to ship so that we know when the samples are coming. The monovalents should be sent to Karen Campbell's attention and the formulated bulks to the Sample Custodian's attention with a concurrent testing letter or lot release protocol (address below). Please note that the Sample Custodian address is for Courier Delivery only (e.g. UPS, FedEx). Please submit:
 
5 lots of each strain (monovalent bulk) - 20 mL each
 
3 lots of formulated bulk - 6 containers of 20 mL of each lot
 
 
Karen Campbell DBSQC/OCBQ/CBER/FDA Building B Room 2410
5516 Nicholson Lane
Kensington, MD 20895
 
Sample Custodian (HFM-672)
Center for Biologics Evaluation and Research
Nicholson Lane Research Center (NLRC)
5516 Nicholson Lane, Building B, Room 113
Kensington, MD 20895
 
Regards, Brenda
 
 
ATTACHMENT – STERILITY TOPIC
 
Topic
Sterility Testing for bulk and finished product
 
Current Status (Optaflu BLA (STN 125408), Section 3.2.P.2 Pharmaceutical
Development, Subsection 3.2.P.2.5 Microbiological Attributes)
 
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Successful aseptic execution of the formulation process is assured by application of validated sterilization processes for equipment to be used and by means of recurring media simulation procedures as well as recurring aseptic operator qualification. In addition, every trivalent bulk is sampled and tested for presence of any microbial contamination. No microbial growth is allowed at this stage. This result is obtained by applying the sterility test method as an in process control. A passing test is evidence for no microbial growth. It assures that the trivalent bulk can be further processed in the filling area without any risk to the subsequent filling process. -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- (Bacterial Challenge Validation R-05-6GPLJSSSC) described in process validation section (see Section 3.2.P.3.5 – Original BLA Filing). ---------------------------------------(b)(4)------------------- represents the boundary between bioburden controlled and sterile product. The filled product is considered to be sterile. To demonstrate integrity of processes and equipment and to verify that filling was successfully performed without microbial contamination, samples are taken from the finished product and tested for sterility as one of the drug product release assays. As described above, the currently applied testing regimen to detect microbial contamination in Optaflu –(b)(4)-------, trivalent bulk and finished product is considered to be suitable. With applying the tests described in Table 3.2.P.2.5-1 (Original BLA filing) to the respective manufacturing steps possible microbial contaminations can be safely detected. There is no risk to patient safety by being exposed to the final product with regard to microbial contaminations.

Regulatory Status

Amendment(s) published May 3, 2012, in 77 FR 26174
Effective Date(s): June 4, 2012
4. Section 610.12 is revised to read as follows:
§ 610.12   Sterility.
(a) The test. Except as provided in paragraph (h) of this section, manufacturers of biological products must perform sterility testing of each lot of each biological product's final container material or other material, as appropriate and as approved in the biologics license application or supplement for that product.
 
Novartis Proposals:
(a) Continue testing scheme as described in Optaflu BLA (STN 125408), as such a
change is not possible for the 2012 flu season, or
 
(b) Add sterility test (to demonstrate formulated trivalent bulk is sterile). Novartis is open to such expectation as laid out by Dr. Rajesh Gupta Deputy Director, Division of Biologics, Standards and Quality Control. However implementation requires completion of several activities to ensure sterility at an earlier stage then filled product:
 
  • Media simulation once new set up established
  • Consideration for reduction of bioburden for pharmacopeia requirements ----------(b)(4)--------------
  • Container Closure Integrity assessment
  • Review of HA loss across sterility filter ---(b)(4)------------ ensure loss is still within specifications. 
Once the new process is validated to demonstrate sterility at bulk stage, Novartis will update the license post-approval for 2013 flu season.