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Vaccines, Blood & Biologics

Record of Telephone Conversation - October 7, 2009 - Prevnar 13

System Info - 113343  SHONE, DEANNA   09-Dec-2009 16:39:03  SHONEDE


Submission Type: Original Application   Submission ID:  125324/0    Office: OVRR  


Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein)


Wyeth Pharmaceuticals Inc.

Telecon Date/Time:  07-OCT-2009 12:00 AM               Initiated by FDA?  Yes

Telephone Number:    


Communication Categorie(s):

Information Request




Telecon Summary:

Discussion on outstanding issues to be addressed either pre-licensure or as PMCs.


FDA Participants:  


Non-FDA Participants:   


Trans-BLA Group: No


Related STNs:  None


Related PMCs:  None


Telecon Body:





Product:  Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein)


Manufacturer:   Wyeth Pharmaceuticals Inc.          


Telecon Date/Time:  7-OCT-2009 11.00 AM     Initiated by FDA?  Yes

Telephone Number: Teleconference was set up by Wyeth


Communication Categorie(s): Information Request


Author:  Tina Roecklein


Telecon Summary:

 Discussion on outstanding issues to be addressed either pre-licensure or as PMCs.


FDA Participants:  

Milan Blake

Willie Vann

John Cipollo

Rajesh Gupta

Julienne Vaillancourt

Michael Smith

Tina Roecklein


Non-FDA Participants:   


Jack Love

Barry Caplan

Kathy Kofsky

Rich Pelt


Telecon Body:


  1. The status of documents requested at the 1 September 2009 meeting was discussed.


    1.                    Concerning Type 5, the plan for characterization of the conjugation process concerning the amount of -----------(b)(4)----------------------------------------------------- results should be received 9 October 2009.
    2.                   Concerning Type 5, the data to address -------------(b)(4)----------- should be received today.
    3.                    Concerning Type 5, the data to address the -------------(b)(4)---------- was received.
    4.                   Concerning a stability indicating assay on drug product, the data and method should be received 9 October 2009.


  1.                   The following are issues that have arisen after the 1 September 2009 meeting.  Requests were made to address these issues pre-licensure.


a.         -----------(b)(4)----------------------------------------------------Specification


The proposed specifications for the serotypes not currently present in Prevnar are much broader that those included in the currently licensed drug product Prevnar. It is not clear how the ranges for these specifications were derived. It appears that many of these ranges are outside of clinical experience. How are these justified?


Wyeth has tightened specifications for ------------(b)(4)----------------------------------  They are willing to commit to operate within the tightened specifications, but not formally establish them until sometime immediately following licensure because of the large amount of documents to be updated.  After discussion of the actual number of documents that required modification due to this change, the number was found to be much smaller than originally stated by Wyeth.  Both Wyeth and CBER agreed that the number of documents required was reasonable.  We stressed that we would like to have the specifications changed before licensure.  Wyeth committed to changing the specifications to the new limits prior to licensure. Wyeth did not feel the need to tighten the specifications for          -------(b)(4)------ but they would look into it.


The one outstanding issue was the specifications for ---(b)(4)------ for            ----(b)(4)-----------  The revised specifications are still outside of the clinical experience.  Wyeth emphasized that they are not able to tighten them any further since doing so would restrict their ability to manufacture the product.  We will have a statistician look over their justification.


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




This data was evaluated during the -(b)(4)- pre-approval inspection.  Wyeth committed to submit the method, validation, and data that they have now.   We would accept a post marketing commitment to establish this assay as a release test with appropriate specifications.



c.     Standard Curve in Quantitative Assays


You have used a standard curve with ----(b)(4)----- points with a calibration by linear regression for the following procedures.  Quantitative analytical methods using a standard curve for calculation of results for unknown samples usually contain (b)(4) or more points, except certain immunochemical methods, where the response is not linear. This is a basic concept in standardization and method development. In your validation studies, you have presented linearity of standard curves using (b)(4) points. Validation of a (b)(4) point standard curve is not acceptable as a substitute of a scientifically sound standard curve in every assay. Further, demonstration of linearity of a standard curve during method validation is not acceptable as a proof of linearity for the method.  According to (b)(4) guidelines, linearity of each method must be demonstrated with actual samples at (b)(4)  points. Several methods used for testing of biological products may not be able to demonstrate linearity at (b)(4) points, particularly the biological and immunochemical methods. In such situation, CBER has accepted demonstration of linearity across the entire range by using 3 points with actual samples. Please commit to re-develop all quantitative methods to incorporate a (b)(4) point standard curve.


During our discussion it was determined that Wyeth had originally validated the assays using (b)(4) point standard curves, but have subsequent to the validation used an SOP that uses (b)(4) point standard curves.  CBER stated that the assays should be performed according to the SOP used in the validation.  Wyeth agreed to evaluate and submit revised procedures in which a (b)(4) point standard curve will be used for the assays in question.  This will be done pre-approval.


I emailed the following list to Jack Love after the teleconference.


  1. 13V-GTM-0001  --(b)(4)-- Asay,  9.1.1 "executed in (b)(4) -  standard curve with (b)(4) points (9.2.1 -  "executed in a                ------(b)(4)------ point standard curve)
  2. 13V-GTM-0005  -------------------------------(b)(4)----------------------------------  9.1.3  "Standard curves are serotype specific and prepared using (b)(4) points … for the –(b)(4)-- Assay and … for the (b)(4) Assay".
  3. 13V-GTM-0013 ---------(b)(4)--------------------------------------- Assay, 9.2.3  "…prepare ----(b)(4)--- standard concentrations within the range of --------(b)(4)-----------------------------
  4. 13V-GTM-0015  ---(b)(4)----- for Serotype 3, 9.0 "Standards for       ------(b)(4)--------- detection will be prepared with ----(b)(4)----- concentrations within the range of --------(b)(4)--------------------- for the ---(b)(4)--- assay and of ----------(b)(4)------------------ for the (b)(4) assay".
  5. 13V-GTM-0022 ----(b)(4)---- Assay,  9.3 "Prepare a standard curve with a ----(b)(4)----------------  over the range of -(b)(4)-------------------------------
  6. 13V-GTM-0045, ------(b)(4)-----, 9.3  Table indicates (b)(4) standard levels of -------(b)(4)------ with Concentrations of -------------(b)(4)-------------------
  7. 13V-GTM-0048  ------(b)(4)------- 9.1  Describes --------(b)(4)--------------------------(b)(4)------ Standard Solutions".


d.                  ------------------------------------------(b)(4)-- Procedure


In the submitted procedure 13V-GTM-0022, Section 13.1 Calculations, the equations for the conversion of results obtained as ---(b)(4)----------- for Serotype (b)(4) includes a factor of (b)(4) and that for Serotype (b)(4) a factor of (b)(4).  These are the ---(b)(4)-----------.  Please explain the basis for these factors and revise procedures.  Wyeth committed to do this pre-licensure.

3.    Wyeth submitted a request for annual reporting of working seeds and a reference in the submission for all relevant protocols.  This has been reviewed and we have no more issues with allowing future working seed changes to be reported in the Annual Report.

4.    The review of the original submission and all early amendments are completed.  These are the issues that we feel need to be addressed prior to approval.  We are currently drafting an Information Request that will be emailed to you summarizing all outstanding issues.  Please be aware that while this Information Request is long, all issues not addressed during this teleconference can be resolved post approval.

Contact FDA

(800) 835-4709
(240) 402-8010
Consumer Affairs Branch (CBER)

Division of Communication and Consumer Affairs

Office of Communication, Outreach and Development

Food and Drug Administration

10903 New Hampshire Avenue

Building 71 Room 3103

Silver Spring, MD 20993-0002

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