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Sep 15, 2010 (Vol. 30, No. 16)

Protein Therapeutic Formulation Issues

Lack of Standards across Most Aspects of Process Impedes Efforts to Improve Quality

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    KBI Biopharma touts a broad range of product-development experience, with an emphasis on formulation, analytical development, process development, and clinical manufacturing.

    The field of protein therapeutics has grown dramatically since the 1980s. Analytical developments along the way have opened the door to understanding protein chemistry and formulations. Current methods to improve the quality of protein formulation development were among the topics discussed at IBC’s recent “Formulation Strategies for Protein Therapeutics” meeting.

    Freeze-drying does not fall under FDA or GMP guidelines; however, there are product stability guidelines. There are also some standards to follow when matching excipients with proteins to prevent protein degradation during freeze-drying. These standards are not foolproof though, and additional work or adjustments to optimize stability of the molecule are often necessary, explained Adora Padilla, Ph.D., scientist I at KBI Biopharma.

    “Typically, it’s a matter of balancing the excipient with the molecule in order to optimize stability, while maintaining product quality. What we’re specifically trying to do is use excipients that are going to give an elegant cake—the appearance of a cake in the vial at the end of the process.” 

    A case study with a molecule highly susceptible to degradation during freeze-drying provided an interesting example. “The main problem was product collapse, which resulted in stability problems and degradation of the molecule upon processing the sample,” Dr. Padilla reported.

    The product collapse was the result of an imbalance of excipients. “It’s important to understand what the state of the excipient is going to be during the process and the balance of crystal and amorphous excipients. Sometimes this has no implications on the stability of the molecule, but in this case it did result in degradation.”

    Overall, the success of freeze-drying depends on the molecule. Some, like antibodies, are more stable in solution; other smaller proteins, such as enzymes, are often freeze-dried. Although there are some rules of thumb, Dr. Padilla thinks it’s not possible to standardize the process. “It’s something that has to be manipulated based on the actual protein.”

  • Synthetic Agents

    Seattle Genetics has developed a technology using synthetic agents called auristatins and linker systems that attach these auristatins to antibodies. The linkers are designed to be stable in the blood and release a potent cell-killing agent once inside the target cell. This approach was designed to reduce toxicity of traditional chemotherapy while enhancing antitumor activity.

    Challenges in formulation development, said Shan Jiang, Ph.D., director of formulation, are due to the complex nature of antibody-drug conjugates (ADCs). Attaching various cytotoxins to the antibody can alter stability and solubility. It’s important to understand degradation pathways and evaluate physical and chemical instability of molecules.

    “One needs to pay close attention to the quality attributes unique to ADCs such as drug-to-antibody molar ratio, sites of drug conjugation, conjugation drug-related impurities, and potency.”

    The company has also developed various analytical methods to better develop ADCs. SGN-35 (brentuximab vedotin), one of its ADCs currently in clinical trials, has shown “encouraging activity in early-stage trials in Hodgkin lymphoma and anaplastic large cell lymphoma patients refractory to several forms of chemotherapy,” reported Peter Senter, Ph.D., vp, chemistry. 

    According to Dr. Senter, a specialized linker technology was developed for its auristatins, a class of antitubulin drugs that includes monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). “The linker incorporates conjugation technology that allows the drug to be attached to the antibody in a way that does not affect its pharmacokinetic properties.”

    The combination of the drug, linker, and conjugation technology, along with the antibodies being used, has contributed to the positive results seen in the clinic to date, Dr. Senter said. He added that the technology is applicable to a wide variety of malignancies, and is also currently in trials for solid tumors with various antibodies.

    “We found that the drug-linker technology we developed applies to almost all antibodies that we’ve looked at—and we’ve looked at hundreds.”

    Although Seattle Genetics has studied its technology with artificial constructs called diabodies, Dr. Senter reported that they have no reason to believe those novel scaffolds will be better than antibodies for drug delivery. “Antibodies are ideally suited for what we’re doing because they stay in circulation a long time and are stable—they are close to ideal carriers for drugs.”


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