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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Review of CMC Information - XYNTHA

MEMORANDUM

Department of Health and Human Services
Public Health Service
Food and Drug Administration
Center for Biologics Evaluation and Research

Date: 26 January 2008
To: The File of STN 125264, Pauline Cottrell & Franklin Stephenson
From: Tim Lee
Through: Basil Golding, M.D.
Director, Division of Hematology
Subject: Review of CMC information in Wyeth's BLA for Antihemophilic Factor (Recombinant), Plasma/Albumin-Free [Moroctocog Alfa (AF-CC)] [Xyntha]

This memorandum summarizes the review of the Chemistry, Manufacturing and Controls (CMC) information in the biologics license application (BLA) for Antihemophilic Factor (Recombinant), Plasma/Albumin-Free submitted by Wyeth Pharmaceuticals, Inc. (Wyeth). This product is also referred to as moroctocog alfa (AF-CC) in the BLA. The proposed proprietary name, "XYNTHA" was reviewed in consultation with CBER's Advertising and Promotional Labeling Branch (APLB) and we concluded that under 21 CFR Part 201, the proposed proprietary name "XYNTHA" be found acceptable.

Wyeth proposed the following indications for Antihemophilic Factor (Recombinant), Plasma/Albumin-Free [Moroctocog Alfa (AF-CC)] [XYNTHA]:

  • Control and prevention of bleeding episodes in patients with hemophilia A
  • Surgical prophylaxis in patients with hemophilia A
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Moroctocog Alfa (AF-CC) is a recombinant antihemophilic factor product manufactured with modifications to the currently licensed manufacturing process for ReFacto bulk drug substance (BDS). The BDS for moroctocog alfa (AF-CC) is manufactured at --------- located in -------------------------------------------------------------------------------------. The modifications are implemented to eliminate the use of animal- and human-derived proteins in the manufacturing process, and are outlined as follows:

  • --------------------------------------------------------------------------------------------------------------
  • Elimination of human serum albumin in the cell culture media
  • Replacement of the monoclonal antibody Sepharose resin with a chemically-synthesized affinity ligand resin (TN 8.2)
  • Introduction of a virus-retaining filtration step ---------------------------

In addition:

  • The new reference standard used in the factor VIII (FVIII) potency assay was calibrated against the 7th FVIII International Standard (IS) using a one-stage clotting assay. This reference standard replaces the one that was calibrated against the 6th IS using a chromogenic substrate (CS) assay. Moroctocog alfa (AF-CC) will be released using a CS assay performed in accordance with the European Pharmacopoeia Assay of Blood Coagulation Factor VIII.

There were no major changes to the manufacturing process used to make the ReFacto final drug product (FDP) for moroctocog alfa (AF-CC). ---------------------------------------------------------------------------------------------------------------------
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This reviewer finds the CMC/product information provided in this application to be supportive of the safety, quality and effectiveness of this product for the proposed indication for the control and prevention of bleeding episodes and for surgical prophylaxis in patients with hemophilia A. Therefore, I find this original BLA to be approvable.

Background

Moroctocog alfa (AF-CC) is indicated for the control and prevention of bleeding episodes and surgical prophylaxis in patients with hemophilia A (congenital Factor VIII deficiency or classic hemophilia). Hemophilia A is an X chromosome-linked hereditary disorder of blood coagulation due to decreased levels of Factor VIII:C and results in bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. Replacement therapy with Factor VIII increases the plasma levels of Factor VIII, thereby enabling a temporary correction of the factor deficiency and the attendant bleeding tendencies.

ReFacto® Antihemophilic Factor (Recombinant) [ReFacto] is a B-domain-deleted recombinant antihemophilic factor product. The active pharmaceutical ingredient (API) is a modified version of recombinant factor VIII [BDDrFVIII or r-VIII SQ] regulated under STN 103779. The BLA for ReFacto was submitted to the FDA on 2 February 1998 and received approval on 6 March 2000. The International Nonproprietary Name (INN) of the API is moroctocog alfa. Wyeth has developed a manufacturing process for the BDS that eliminates the use of human- or animal-derived proteins from the manufacturing process and in addition incorporates a virus-retaining filtration step. The BDDrFVIII manufactured using this albumin-free cell culture process is referred to as moroctocog alfa (AF-CC) and ReFacto AF in the early developmental phase of the project. Wyeth submitted a BLA under STN 125264 for moroctocog alfa (AF-CC) on 25 April 2007.

To distinguish references to the current licensed ReFacto from moroctocog alfa (AF-CC) whose investigational studies have been conducted under BB-IND -----, Wyeth refers to the former as ReFacto or ReFacto (current) and the latter as moroctocog alfa (AF-CC) in the BLA. In some instances, the term ReFacto AF is used because of historical reference to this product's development.

Moroctocog alfa (AF-CC) is formulated as a sterile, non-pyrogenic, lyophilized powder preparation for intravenous (IV) injection. It is provided in single-use vials containing the labeled amount of FVIII activity in International Units (IU). Each vial contains nominally 250, 500, 1000, or 2000 IU per vial. Upon reconstitution with the supplied diluent (0.9 % Sodium Chloride solution), the product is a clear to slightly opalescent, colorless solution that contains sodium chloride, sucrose, L-histidine, calcium chloride and polysorbate 80.

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