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Responses to Complete Response Letter Memo, January 21, 2010 - Flublok


DATE:            January 21, 2010
FROM:            Maryna Eichelberger, PhD
THRU:            Jerry Weir, PhD
CC:                  Matthew Sandbulte, PhD
                        Arifa Kahn, PhD
SUBJECT:      BLA STN 125285, Responses to Complete Response Letter and subsequent information requests
PRODUCT:     Influenza recombinant HA trivalent
SPONSOR:     Protein Sciences Corp
This review memo covers Protein Sciences’ responses to CBER’s Complete Response letter, comments 1, 2, 5d-12. Responses are summarized as follows:
Comment 1:
a. Data submitted for 2007 and 2008 monovalent bulk lots do not demonstrate consistent production of rHA from H1, H3 and B strains. Multiple lot failures suggest controls were not in place to ensure consistent manufacture.
b. A 2009 validation report provides data for all ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.
c. The 2009 validation report includes data to support validation of ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)---------------------------------------------------------------------------------------------------------------------------------. Specifications were met by all monovalent bulk validation lots, but manufacture of H1 lots after completion of validation, resulted in OOS results. The investigations into these deviations were not satisfactory, with root causes identified that are not supported by the available information. Manufacture of B rHA is not consistent and root cause has not been identified. Modifications are currently being explored, and the sponsor states that once a successful engineering run has been performed, 3 validation runs will be performed, with changes and completed validation submitted for review.
Comment 2a-i. The data submitted to characterize conditions and support step limits were acceptable.
Comment 3:
a. Data were submitted to support a minimum potency dose of (b)(4).
b. ---(b)(4)---- to achieve minimum potency at 16 weeks was appropriately calculated from stability studies. Minimum potency specifications for product at release is -------(b)(4)---. This is acceptable.
c. The product upper specification for potency is (b)(4). Clinical data were used to support this value. This is acceptable.
d. The upper specification for total protein is ---(b)(4)-----. Clinical data were used to support this value. This is acceptable.
e. Data from batches produced in 2009 support the suggestion that it is rare and unusual to achieve SRID values greater than absolute amount of protein measured by BCA assay. The sponsor has identified an upper limit ------(b)(4)------------------------------; OOS results will be investigated. The sponsor presented data suggesting total protein is a better correlate of immunogenicity than SRID values. A statistical analysis of this correlation was not provided. An alternative potency assay has not been approved.
f. Since there is no data to support inclusion of ---(b)(4)--- as a product specification, the sponsor will not add this as a specification. Based on prior clinical lots, the upper limit specification for total protein has been set at  ---(b)(4)----. This is acceptable.
g. DNA content is consistently less than ---(b)(4)-----, and the sponsor provided data to support residual DNA having --(b)(4)--. This is acceptable.
Comment 4:
a. Particulates were visible to the eye in some monovalent batches prepared in 2007 and were present in all batches prepared in 2008. The sponsor initiated studies of aggregation in preparations from each strain, however, the data has not been submitted for review at this time.
b. The sponsor agreed to include a statement to store the product in the dark.
c. There is no stability data for product filled at Hospira that meet release specifications.
d. Potency was used to establish a hold time for drug substance of ---(b)(4)-- for H1, --(b)(4)-- for H3 rHAs, and --(b)(4)-- for B rHA. During this period of time, at least (b)(4) of potency was retained in lots manufactured in 2008 and 2009.
Comment 5:
Reviewed by cell substrate product specialist (DVP)
Comment 6:
a. The origin and passage history for each strain manufactured in 2008 and 2009 were provided.
b. The sponsor provided parameters for designated reference sequence. Since the rHA they have cloned from B/Brisbane/60/2008 is not identical to a reference sequence, we expect demonstration that this product is antigenically similar to the recommended vaccine strain. This demonstration has not yet been provided.
c. An acceptable SOP for screening and selection of HA clones was provided.
d. Data provided support integration of HA at one site of the baculovirus genome.
Comment 7: An acceptable plan for overall manufacturing optimization of new strains was provided.
Comment 8:
a. An acceptable description of ----(b)(4)---- assessment of contamination was provided.
b. The sensitivity of the bioburden tests was provided. This response is acceptable.
c. Data to support removal of –(b)(4)-- was provided in the submission of December 18, 2009. This will be reviewed together with the response to the 11 January, 2010 CR letter.
Comment 9: Data support clearance of baculovirus in amounts that are similar or greater than in the starting material. This is acceptable since the absence of live baculovirus is verified by testing the ----(b)(4)----.
Comment 10:
a. Responses to i, ii and iv were acceptable. Data to demonstrate accuracy of the purity assay when a standard larger than –(b)(4)-- is used has been submitted (December 18, 2009) and will be reviewed with the response to the CR letter of January 12, 2010.
b. (b)(4) assay has been modified to include a standard at (b)(4). This is acceptable.
c. The SOP for the DNA –(b)(4)-- assay was submitted together with a validation report. Results to support linearity and limit of detection in the presence of ---(b)(4)-------- protein were submitted December 18, 2009 and will be reviewed together with the response to the CR letter of January 12, 2010.
d. The standard used in the endotoxin assay is acceptable.
e. ---(b)(4)------ will be added as a vaccine excipient. The sponsor plans to demonstrate the absence of this compound to support removal of this from product description. This is acceptable.
f. The validation of Tween 20 assay was submitted December 18, 2010 and will be reviewed together with the response to the CR letter of January 12, 2010.
g. The justification for this formula was acceptable.
Comment 11:
a. A description of shipping and storage conditions is acceptable.
b. Batch record sheets were provided. These are acceptable.
c. The data from mixing studies are acceptable.
d. Process validation reports for runs 2 and 3 have not been provided.
e-f. Reviewed by DMPQ.
Comment 12: Issues raised during pre-licensure inspection in July 2008 were resolved. Pre-licensure inspection in October 2009 identified issues that have not been resolved to date.
Conclusions: Data provided do not support consistent performance of downstream process steps during manufacture of rHA from H1 and B strains. A number of outstanding items have been identified, including need for data to support validation of final drug product formulation and filling.
Review of resubmission and associated responses to information requests:
CBER comments from the CR letter of August 29, 2008 are shown in italics, followed by a summary of each response. Comments included in the January 11, 2010 Complete Response Letter are shown in bold.
1.     We do not consider the validation of manufacturing process to be complete for the following reasons:
a.      The data provided are insufficient to assess consistency of the manufacturing process. Please provide tabulated results of critical process parameters and in-process tests of product yield for each manufacturing step for H1, H3 and B monovalent bulk lots prepared in 2007 and 2008.
Data provided for 2007 and 2008 production do not demonstrate consistent manufacture of H1, H3 and B strains. In addition, multiple lot failures in 2008 were a cause for concern. When asked to evidence that problems had been resolved (information request July 30th, 2009 comments 1aA and 1aB), the sponsor stated that several steps had been taken to enhance manufacturing consistency as a result of 2008 corrective actions. These included changes in planning --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Validation reports were not submitted with the CR letter response. Since this would potentially provide complete data for 3 batches of H3, we requested an interim validation report in a telecom on May 27, 2009 as soon as it was available. An interim report
31 Pages Determined to be Not Releasable: (b)(4)