Biopharmaceuticals: Approval Trends in 2007 - More than 70% of the products were produced in mammalian cells. - BioPharm International


Biopharmaceuticals: Approval Trends in 2007
More than 70% of the products were produced in mammalian cells.

BioPharm International
Volume 21, Issue 10

Both of these gonadotropic hormones are dimeric glycoproteins, consisting of identical 92 amino acid α subunits and a distinct β subunit (111 amino acids in the case of FSH; 121 amino acids in the case of LH). The distinct β subunit confers biological specificity on these hormones. Both subunits are glycosylated.

Pergoveris was approved for general medical use in the EU in June 2007. It is indicated for stimulating follicular development in women with severe LH and FSH deficiency (and who are therefore usually infertile). FSH naturally stimulates follicular development with subsequent rupture, and hence, egg release being largely under the influence of LH.

Manufacturing the active substances entails separate cell culture of the anchorage-dependent producer CHO cells in microcarrier -containing bioreactors. The products are subsequently purified by multiple chromatographic steps and are then combined in a fixed concentration. The final product is filled into vials and lyophilized. Each vial contains 11 μg (150 IU) FSH and 3 μg (75 IU) LH.

Pergoveris is typically administered once daily until the recipient has developed a suitably matured follicle. This may take up to five weeks.

Some clinical data generated during previous studies of the individual active ingredients were presented in support of safety and efficacy. Additional studies of the combination product, including bioequivalence studies, were also conducted. The most common side effects noted were headaches, injection site reactions, and ovarian cysts. The product is manufactured and marketed by Serono (Geneva, Switzerland).

Retacrit (epoetin zeta) is a recombinant form of human erythropoietin produced in a CHO cell line. It is a biosimilar product with Janssen-Cilag's EPO Eprex/Erypo having served as reference medicine.

The product is identical to both reference and native EPO in amino-acid sequence. A combination of HPLC, NMR, and Mass spectrometry-based analysis indicated the molecule's overall glycocomponent to be substantially similar to the reference EPO. The number of glycoforms devoid of the O-linked glycan chain was slightly higher although the level of sialylation was similar. Overall, the product's carbohydrate content was judged to be free of any unusual or potentially immunogenic structures or epitopes.

Retacrit gained approval in the EU in December 2007. Its approved indications are similar to those of Abseamed, Binocrit, and Epoetin alfa Hexal. Specifically, it is indicated for the treatment of anemia associated with chronic renal failure and for anemia accompanying the chemotherapy of certain cancer types. It also can be used to increase the yield of autologous blood from patients in a predonation program.

The upstream element of product manufacture is based on a feed-batch cell-culture process. The cell-culture media is proteins, insulin, and free of antibiotics, and is also devoid of ingredients derived from human or animal origin. After initial recovery, the product is purified by a combination of chromatographic techniques, and downstream processing also incorporates a nanofiltration-based virus-removal step. The excipients added include phosphate buffer components, calcium, and sodium chloride, polysorbate 20, and several amino acids (glutamic acid, glycine, isoleucine, leucine, phenylalanine, and threonine). The final product is filter sterilized and aseptically filled into presterile syringes. The product is commercially available at active ingredient potency levels ranging from 3,333 IU/mL to 40,000 IU/mL.

Retacrit's exact dosage regime will be tailored to the individual patient. The product can be administered subcutaneously to patients receiving chemotherapy and intravenously for other indications.

Product comparability to the reference medicine was established primarily by two studies involving a total of 922 patients displaying anemia associated with chronic kidney disease, as well as a third study in which the product was administered to 261 cancer patients receiving chemotherapy. Primary endpoints measured were invariably generation and maintenance of blood hemoglobin levels. The most common adverse effect associated with product administration was an increase in blood pressure.

Retacrit's active ingredient is manufactured by Norbitec GmbH (Uetersen, Germany). Netherlands-based Hospira enterprises B.V., markets the product.

Silapo. This product, along with its indications and all other characteristics, is identical to Retacrit above. It differs only in the tradename used and in that Germany-based STADA Arzneimittel AG, holds marketing authorization throughout the EU.

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