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

Cervarix manufacture requires separate recombinant production of the major caspid (L1) proteins of HPV strains 16 and 18. Subsequent to upstream processing the caspid proteins are released from the cultured insect cells by osmotic shock. This is followed by multiple chromatographic purification steps, and nanofiltration. The purified L1 protein antigens are then adsorbed separately onto aluminium hydroxide. An adjuvant material, monophosphoryl lipid A (MPL), is also separately adsorbed onto an additional aluminium hydroxide. MPL is a detoxified derivative of the lipopolysaccharide moiety of the gram negative bacterium Salmonella minnesota. The final vaccine product is then produced by mixing defined amounts of all three adsorbed species, along with sodium chloride and phosphate buffer components as excipients. The final vaccine suspension is filled into either vials or syringes. Each dose contains 20 μg of both HPV type 16 and type 18 L1 caspid proteins.

Product administration (to girls and women 10 years and older) is by intramuscular injection and a typical administration schedule entails follow-on doses one and six months after administrating the initial dose. Clinical trials assessing product safety and efficacy involved more than 21,000 females between the ages of 10 and 25, and clearly illustrated a protective effect. The most common side effects noted were headache, muscle pain, and injection site reactions. The product is manufactured and marketed by GlaxoSmithKline Biologicals (London, UK).

Epoetin alfa Hexal. This product, along with its indications and all other characteristics, is identical to Abseamed and Binocrit. It differs only in the tradename used and in that Hexal biotech Forschungs GmbH, Germany, holds marketing authorization throughout the EU.

Mircera (methoxy polyethylene glycol epoetin beta) is a PEGylated recombinant form of human EPO. The erythropoietin used to generate Mircera is the active substance of Neorecormon (epoetin beta; Roche's recombinant EPO first approved for general medical use in the EU in 1996). The PEG moiety used is methoxypolyethylene glycol–succinimidyl butanoic acid (PEG–SBA), a 30 kDa linear chemically activated PEG. When co-incubated under appropriate conditions, the PEG–SBA spontaneously forms amide linkages with either EPO's N-terminal amino group or with the ε-amino group of an accessible surface lysine residue (Lys 45 or Lys 52). The final product generated is a 60 kDa monopegylated product.

Mircera was approved for general medical use in both the EU and the USA in 2007. The approved indication in both regions is restricted to the treatment of chronic kidney disease, and the label explicitly states that the product's safety and efficacy in the context of other indications has not been established. In fact, one dose-ranging clinical study aimed at assessing the product for treating chemotherapy-induced anemia was terminated prematurely because of a significantly greater death rate amongst patients receiving the product.

The recombinant EPO is manufactured by initial cell culture of the producer CHO cell line in serum-free media. Purification entails five sequential chromatography steps (dye affinity, hydrophobic interaction, and hydroxyapatite chromatographies, followed by a reverse phase HPLC step and finally an ion-exchange step). The purified EPO is then co-incubated with the chemically activated PEG, followed by chromatographic separation of the PEG–EPO conjugate from unreacted monomers or reaction by products. Phosphate buffer constituents, mannitol, poloxamer 188, sodium sulphate, and methionine are added as excipients and the filter-sterilized product is filled into glass vials or prefilled syringes.

In vitro studies indicated that the PEGylated EPO has a lower affinity for the EPO receptor compared to unmodified EPO. However, in vivo studies (using both mouse and dog models, and echoed in clinical studies) showed the PEGylated product to be a more potent stimulator of erythropoiesis in terms of magnitude and, in particular, duration of response. These effects are likely indirect, being linked to reduced product-tissue penetration and retardation of product elimination. Although exact dosage regimes are tailored to individual patients, typical regimes entail product administration once every 2–4 weeks. Neorecormon, in contrast, is administered at least once weekly. The most common adverse reaction associated with Mircera administration is hypertension. The product is manufactured and marketed by Roche (Basel, Switzerland).

Pergoveris (follitropin alfa/lutropin alfa) contains twin active substances—recombinant human follicle stimulating hormone (FSH; follitropin alfa) and recombinant human luteinizing hormone (LH; lutropin alfa). Both are separately produced using an engineered CHO cell line. Both active ingredients are already approved individually for general medical use as stand-alone products (tradenames Gonal F and Luveris, respectively).

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