Mid-cycle 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: 22 October 2007 
To: The File of STN 125264, Pauline Cottrell & Franklin Stephenson 
From: Tim Lee 
Through: Basil Golding, M.D.
Director, Division of Hematology 
Subject: Mid-cycle Review of CMC information in Wyeth's BLA for Moroctocog Alfa (AF-CC) 


This memorandum summarizes the mid-cycle review of the Chemistry, Manufacturing and Controls (CMC) information in the original biologics license application (BLA) for moroctocog alfa (AF-CC) submitted by Wyeth Pharmaceuticals Inc. (Wyeth). At the mid-cycle meeting, the review committee did not identify any major issues that would prevent the approval of this submission.

The proposed indications for moroctocog alfa (AF-CC) include:
•Control and prevention of hemorrhagic 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 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:
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•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 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 FVIII.

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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Background

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] regulated under STN 103779. The BLA for ReFacto was submitted to the FDA on 2 February 2 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 later 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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