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Vaccines, Blood & Biologics

DPQ Review Memo, September 6, 2011 - MenHibrix


Date:         September 6, 2011           

To:            Joseph Temenak, HFM-481
                  Chair, BLA Review Team

From:       Rajesh K. Gupta, Ph.D., HFM-680
                  Deputy Director, Division of Product Quality (DPQ) and Lab Chief, Product Quality Laboratory

Through:  William McCormick, Ph.D., HFM-680 Director, Division of Product Quality (DPQ)

Subject:    STN 125363 –– Amendment 0.12 – Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine, Hib-MenCY-TT, MenHiberix®, Letter Ready comments for communication to GSK

Cc:             William McCormick, Ph.D., HFM-680
                  Willie Vann, Ph.D., HFM-437

On May 7, 2010, DPQ review memo was submitted and all comments from that review memo were communicated to the sponsor in a complete response (CR) letter on June 11, 2010. GSK provided response to the comments in CR letter in an amendment 0.12 received on April 15, 2011. On August 29, 2011, DPQ submitted a review memo on GSK’s responses to DPQ’s comments that were communicated in the CR letter. This memo summarizes DPQ’s comments in a letter ready format for communication to the sponsor.
In their response a number of comments in the CR letter, GSK has proposed to address these by additional studies to be performed by sponsor, which will be completed by 4Q2011. DPQ agrees with the experimental plans and rationale for completing these studies by 4Q2011. Based on these responses, following commitments should be communicated to the sponsor.

  1. In response to comments 42b, 42d, 42f, 42i and 42h, you commit to perform additional studies on linearity, accuracy and precision for the following methods using drug substance and drug product samples and provide additional data by 4Q2011.
    1. Polysaccharide Content -----------------(b)(4)---------------------------
    2. Polysaccharide Content -----------------(b)(4)------------------------------
    3. Polysaccharide Content -----------------(b)(4)-----------------------------
    4. Determination of ----(b)(4)----- Content in (b)(4) Conjugate; and
    5. Determination of PSC and PSY Content in the Final Containers by -----------(b)(4)--------
  2. In response to comments 43b, 43e, 43g, you commit to perform additional studies on linearity using drug substance and drug product samples instead of assessing linearity from the standard curve for the following methods and provide the additional data by 4Q2011.
    1. Polysaccharide Content ---------------------(b)(4)----------------------
    2. Polysaccharide Content ---------------------(b)(4)-------------------------
    3. Determination of ---------------------(b)(4)-----------------------
  3. In response to comments 44a and 44b, you commit to complete the accuracy validation experiments for the following methods.
    1. Polysaccharide Content -------------------(b)(4)----------------------
    2. Determination of -------------------(b)(4)----------------------
  4. In response to comments 45a, 45c, 45g and 45f, you commit to complete the precision validation experiments across the range of the method using samples from drug substance and drug product for the following methods.
    1. Polysaccharide Content -----------------(b)(4)----------------------
    2. Polysaccharide Content by -----------------(b)(4)----------------------
    3. Determination of --------------------(b)(4)----------------------
    4. Determination of PSC and PSY Content in the Final Containers by ----------(b)(4)------------
  5. In response to comment 49 you commit to perform additional ---(b)(4)--- studies using ----(b)(4)------ samples in parallel, to assess the -----(b)(4)--------------------------------------------------------------------- determination method.

Additionally, DPQ needs further information in response to other comments in the CR letter. Following comments should be communicated to the sponsor as part of the CR letter or information requests (IR) in the next regulatory communication letter.

  1. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
    1. Classify the procedure as a limits test rather than a quantitative impurities procedure.
    2. Since the lowest standard is (b)(4) micrograms/L, results should be reported as (b)(4) micrograms/L when applying the bias correction.  This will also be the product specification.
    3. Clarify that the LOQ stated in the conclusion is micrograms/L not micrograms/mL.
  2. In response to comments 42c, 42e and 42g with regard to linearity of Free Saccharide methods, you stated in Report 9000000693 RVM0l0, Section 3.4 that “theoretical concentrations were calculated by taking the mean of the experimental concentrations (mean of the individual values from 4 independent series)”.  Based on this statement and the data provided, a circular logic has been applied, i.e. experimental results are used to establish the theoretical concentrations to which these results are being compared. However, data provided to support precision and accuracy could be used to demonstrate linearity of these methods.  For example, accuracy has been demonstrated by --(b)(4)-- of samples with (b)(4) saccharides at (b)(4) concentration levels and (b)(4) replicates at each level. Please re-analyze these data in Report 9000000693 RVM0l0 Section 3.6 to demonstrate linearity of Free Saccharide method for Hib-TT bulk conjugate. Similarly, please re-calculate linearity of Free Sacchride methods for MenC-TT and MenY-TT bulk conjugates.
  3. In response to comment 53 regarding the ------------------(b)(4)------------------ of MenC-TT and MenY-TT Bulk Conjugates by ----(b)(4)---- (SOP 9000006776), you provided the criteria for column selection and validation documents. Please provide following information from the validation study.
    1. In the validation report, there are (b)(4) lots of ---(b)(4)--- tested.  Please provide a description of the ------(b)(4)----- sample and the relevancy of this sample type to the product. It is stated that the unusually high recovery (b)(4) of ----(b)(4)---- is still under investigation. Upon the conclusion of investigation, please provide a copy of the report and root cause for this discrepancy to FDA.
    2. The test result of Hib FC-lot ---------(b)(4)----------, which is listed as a sample in page ‘16 of 32’ of the validation protocol, cannot be found in the validation report. Please submit the test result for this sample or provide a reason as to why it was not included in the validation report.
    3. Please submit an SOP for (b)(4) determination of conjugate bulks with the ------(b)(4)----- to replace SOP 9000001926. 
  4. In response to comment 67a, you provided a validation report for the sucrose method. The evaluation of linearity for this method by (b)(4) in the validation report 9000011398RVM001/01/01 is described as being applied to “standards solutions” and “evaluated by establishing a linear regression model between the back-calculated concentrations and the theoretical concentrations …”.  It is unclear whether the “standards solutions” represent calibration standards or “validation standards” in placebo matrix as described in Section 1.1.  The meaning of “back-calculated” is unclear, but appears to be a circular calculation of these standards against themselves.  However, the data presented in Sections 1.2 “Response fonction” and 1.7 “Specificity” adequately support linearity across the range of the method for both calibrants and analyte in placebo matrix.  If this data are suitable, please re-analyze these data to demonstrate linearity for this test method.

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