ABSTRACT
The state-of-the-art treatment for hemophilia A is replacement therapy with recombinant
factor VIII (rFVIII) made possible by genetic engineering advances. Currently, there
are four different products licensed and available for hemophilia A patients. All
are produced by recombinant mammalian cells in large-scale fermenter cultures, purified
to high purity, formulated in stable formulations and freeze dried. The first-generation
products Recombinate® and Kogenate® (also sold as Helixate® by Aventis) are characterized
as full-length human factor VIII molecules and formulated using human serum albumin
as a stabilizer. The second-generation product ReFacto® contains an improved albumin-free
sucrose formulation and incorporates advanced antiviral safety procedures in the manufacturing
process. It is a truncated B region-deleted form of factor VIII (FVIII) that makes
use of a nonhuman peptide linker 14 amino acids in length to connect the 80 and 90
kD subunits. The most recently licensed rFVIII product is the second-generation Kogenate
product called KOGENATE®Bayer/Kogenate® FS, which combines the advantages of the human
full-length FVIII molecule with an albumin-free, sucrose-based synthetic formulation
as well as an improved viral safety profile. In this article, the manufacturing processes
for each of the four different products are discussed in detail, focusing on expression
systems and cell lines, culture medium, technical culture systems, purification process
(including viral removal potential), and final formulation.
KEYWORD
Mammalian cell culture - virus safety - Helixate® - Kogenate® - KOGENATE® - Bayer/Kogenate®
- FS - Recombinate® - ReFacto®
