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Sep 15, 2011 (Vol. 31, No. 16)

Timing Is Everything in Protein Formulation

Choosing When and How to Proceed Depends on Available Resources and Competition

  • Crystalline Work-Around

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    Althea has expertise in formulations such as liposomes and nanoparticles, conjugates, crystallized proteins, protein concentration/buffer exchange, adjuvants, and viscous products.

    Althea’s protein crystal technology supports the switch from intravenous to highly concentrated subcutaneous therapeutic protein delivery, and with it self-administration, long-acting formulation, and lifecycle extension. Protein crystals are related to but should not be confused with CLECs (crosslinked enzyme crystals), which Althea inherited through its acquisition of Altus Biologics.

    Protein crystal formulations are delivered as suspensions of 5–10 micron particles, not solutions. When formulated as suspended solids, proteins are far less prone to stability and aggregation issues. Since the drug is significantly less viscous than highly concentrated protein solutions, it may be delivered through a fine-gauge needle.

    For example, it takes less than one minute to load a 1 mL syringe with crystalline infliximab (Remicade) at a nominal concentration of 200 mg/mL. By comparison, a 1 mL syringe of soluble infliximab at only 150 mg/mL takes 20 minutes to load. Similarly, injection of the crystalline product takes 20 seconds compared with 100 seconds for the solubilized protein.

    John Hicks, director of corporate development at Althea, is quick to note that alternative subcutaneous injection formulations exist, “although there aren’t many, and few achieve high drug concentrations.” Most notable is Halozyme’s partnership with Roche to develop subcutaneous Rituxan and Herceptin using a recombinant hyaluronidase technology.

    “It appears that they can deliver subcutaneously,” Hicks says. “However with Herceptin, Roche had to invest $185 million on a proprietary delivery device to target 5–10 minute administration of injections as high as 12 mL. Pain becomes a serious issue with injections significantly larger than 1.5 mL.”

    The switch to subcutaneous administration involves an IP or lifecycle component—companies hurrying to switch before their IV patents expire. But healthcare economics is undoubtedly the true driving force. “Why bring a patient into a hospital or an infusion center when the treatment can be administered in an office or even self-administered?”

    Crystalline suspensions don’t necessarily require longer development times than conventional platforms, but they do require a somewhat different skill set. Chemists may use any reagent they like to produce crystals, whereas bioprocessors are restrained to pharmaceutically acceptable buffers under conditions that promote rapid crystallization at high yield. Althea claims yields of greater than 90% in 24 hours.

    Protein crystallization does not change the state of the native protein, yet Althea has met with resistance to the technology.

    “There’s a knee-jerk reaction against injecting crystals, most likely based on the potential for immunogenicity. We haven’t seen any in the weekly hGH trials so far,” says Hicks. “Besides, insulin crystals have been used for years on a daily basis, for example Lilly’s Humalog, which is a mix of soluble and crystalline insulin.”

  • The Super-Excipient

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    There is no such thing as a universal excipient, but albumin achieves several formulation objectives compared to sugars, amino acids, and detergents.

    Albumin is a critical ingredient for cell culture, formulated proteins, and other biotech products. It binds to and stabilizes important molecules and ions, prevents aggregation and nonspecific adsorption onto glass, and serves as an antioxidant.

    Aralast (Baxter), Kogenate (Abbott), Intron A (Merck), and Avonex (Biogen Idec) are just a few of the products formulated with albumin as an excipient.

    Because of cost, bovine albumin was at one time preferred over human albumin. However, the trend toward serum-free and animal component-free media, and injected/infused products, has led to significant demand for recombinant human albumin (rAlbumin).

    “Albumin is an extremely useful excipient in protein drug formulations, particularly for drugs that are self-administered,” says Dermot Pearson, marketing director at Novozymes Biopharma.

    “There is no such thing as a universal excipient, but albumin achieves several formulation objectives compared with SADs.” Pearson is referring here to the acronym for common bioformulation excipients: sugars, amino acids, and detergents.

    SADs are known to stabilize products in lyophilized forms, but their ability to stabilize proteins formulated as liquids has yet to be proved on a broad basis, according to Pearson.

    Novozymes specializes in recombinant human albumin manufactured in yeast. Recombumin®, the firm’s lead product, and albucult® are used in drug and vaccine manufacture.

    Recombinant human albumin can assist in both initial formulation and lifecycle-management reformulations. Novozymes’ customers are becoming interested in fine-tuning their formulations at earlier stages in the clinical development process.

    For companies producing monoclonal antibodies, recombinant albumin can help resolve formulation issues earlier, according to Pearson, particularly when initial efforts using SADs fail.

    Similarly, he maintains that the excipient “can help build security and maintain market share and exclusivity” for products nearing patent expiration.

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