Formulation, Characterization, and Stability of Protein Drugs: Case Histories

Volume 9 of the series Pharmaceutical Biotechnology pp 343-364

Formulation Development of an Antifibrin Monoclonal Antibody Radiopharmaceutical

  • Madhav S. KamatAffiliated withPharmaceutical Development, Centocor Inc.
  • , Glen L. TolmanAffiliated withPharmaceutical Development, Centocor Inc.
  • , John M. BrownAffiliated withPharmaceutical Development, Centocor Inc.

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These studies have shown that formulation development of a monoclonal anti-body radio-immunoscintigraphy agent is a challenging task involving a number of issues related to the radiochemistry of labeling as well as the stability of the antibody. Through a systematic approach, as described in this study, a stable and efficacious product of high quality can be developed in a rational and efficient manner. In developing an optimized formulation of Tc-99m—antifibrin Fab’ for use in immuno-scintigraphy of DVT, a number of critical components were examined in regard to technetium-labeling chemistry and the ability of the formulation to support the long-term stability of the product. It was found that the addition of glucarate as a transfer ligand, SnCl2 as a reducing agent, and neutral-to-acidic pH of the solution were essential for optimum radiolabeling of 0.5 mg of antifibrin Fab’ to a desired activity of 25 mCi of Tc-99m. The lyophilization of the final product was also required to further stabilize both the antifibrin Fab’ fragment and the reducing agent. The addition of carbohydrate as bulking agent and lyoprotectant and inclusion of EDTA as a chelating agent further improved the performance of the formulations, resulting in products with long shelf-life.

Many of the principles described in this study are not only useful in developing a technetium-based immunoscintigraphic agent but are also applicable to other immunopharmaceuticals, including products involving delivery of radionuclides, drugs, and toxins for immunotherapy of cancer and other diseases.