Importance of Formulation
“Formulation composition is important when devising a product lyophilization process. For example, bulking agents may be added when one wants to freeze-dry small amounts of potent material, protective agents are added when one is dealing with heat-sensitive enzyme, antibody, or protein to prevent aggregation, and thermal stabilizers like dextran or PEG may be added to remedy a situation where a freeze-drying cycle is protracted due to the formulation having a low critical temperature,” explains Kevin Ward, Ph.D, director of R&D at BTL.
Developing the right formulation depends on factors such as the final dosage form of product, the stage of clinical development, and the desired product concentration. For example, many antibody therapeutics require high product concentration to demonstrate efficacy after subcutaneous (SC) or intra-muscular (IM) administration. In such cases, freeze-drying may be useful not only for maintenance of product stability, but also to facilitate concentration of product via reconstitution in the small volumes (£2mL) required for SC and IM injection.
KBI BioPharma (www.kbibiopharma.com) adopts a multi-step approach to formulation development. The company is a contract development organization for analytical, formulation, and process development for biotherapeutic proteins. The conformational and thermal properties of a product are first characterized using biophysical techniques such as differential scanning calorimetry, circular dichroism, FTIR, and fluorescence spectroscopy.
Statistical design of experiments is used during preformulation development to identify the optimal formulation conditions (buffer type, pH, ionic strength, excipients), which result in chemical and conformational stability of the product. The final concentrations of product, bulking agents, and cryoprotectants are optimized during freeze-drying cycle development.
“Technology transfer to the manufacturing facility is a critical element for a successful production run. Development is usually performed at a smaller scale using partial product loads, based on API availability and cost. Differences in scale as well as freeze-dryer design differences must be evaluated as part of tech transfer. Hence, involvement of the development house with production facility is imperative for successful process transfer,” states Tim Kelly, Ph.D., vp of biopharmaceutical development at KBI BioPharma.