Biopharmaceuticals

• Steps in the manufacture of biologicals:

  Upstream processing

  • Cell cultivation
  • Cells harvested from medium

  Downstream processing

  • Solid-liquid separation
  • Concentration
  • Purification
  • Quality control and assurance
• Issues with biopharm formulation

  • Proteinaceous nature therefore denatured easily
  • Large molecules (complex)
  • High doses
  • Stability issues
• Oxidation

  • Methitione on Fc and cysteine residues on Fv susceptible
  • Caused by oxidising agents, high T, UV light
  • Effect: reduced efficiency, impact interaction on Fv
• Delamination

  • Glutamine and asparagine converted to glutamic and aspartic acid
  • Cause: high T, ionic strength and extreme pH
  • More acidic form of antibody due to carboxylic group
• Fragmentation

  • Occurs at natural flexure sites, such as hinge peptide between Fc and Fv domains
  • Consequence: reduction in efficency and biodistribution
• Aggregation

  • Low conc liquid protein formulation can suffer adsorption to container walls and less conc over time
  • High conc can suffer from aggregation and increase in viscosity
• Strategies to stabilise antibody formulations

  • Lyophilization: solution frozen, placed under vacuum, solvent sublimates leaving solid only.
  • Simple formulations including surfactants/antiaggregants Such as polysorbate 20
• Biosimilars

  • Def: drug that is similar to a biopharmaceutical that has already been approved
  • Different from "generics" bc large complex molecules