Identify molecular liabilities and/or select optimal lead molecule

The aim of formulatability studies is to identify molecular liabilities, in conjunction with in silico modeling, that can negatively affect drug product stability or quality during the drug product’s lifetime, from manufacturing to administration to the patient. This information can be extremely valuable for selecting the optimal lead molecule from among a panel of potential molecule candidates or variants. It is also essential for selecting the appropriate drug product development strategy, including tailoring formulation development studies to address the molecule’s specific shortcomings, thus ensuring its clinical and commercial success.

Our Drug Product Services (Lonza DPS) team has a wide experience in performing and evaluating formulatability studies, to identify/flag potential development risks, and provide means to mitigate those risks. 

The panel of in-vitro formulatability studies typically includes:

  • Assessment of chemical liabilities, such as deamidation, oxidation, fragmentation, glycation
  • Assessment of biophysical characteristics, such as isoelectric point (pI) and hydrophobicity, as well as colloidal and thermal behavior as a function of formulation conditions and assessment of liabilities to physical stresses
  • Assessment of rheological properties, particularly in case a high concentration formulation is required

  • Assessment of Chemical Liabilities
    Molecules and clinical candidates cannot only vary in their pharmacological or toxicological properties. They can also vary in their liabilities towards degradation, and some clinical candidates molecules may be more appropriate for a given target product profile than others. 

    Chemical degradation products may be critical quality attributes (CQA), i.e. impact efficacy and/or safety, for example deamidation in CDR impacts binding (Harris et al) and oxidation in an antibody may impact FcRn binding and thus pharmacokinetics (Stracke et al), or may impact Immunogenicity.

    Our DPS team supports evaluation of chemical-degradation endpoints, including oxidation, deamidation and clipping, performs forced degradation and stress studies, including thermal, pH, light and other stress conditions, to assess the impact of degradation on the mode of action such as binding. This enables us to evaluate the criticality of a degradation route (CQA assessment).

  • Colloidal stability refers to stability between protein monomers, and helps to evaluate tendencies for self-association, and thus, risks for aggregation or precipitation, phase separation, viscosity and/or turbidity.

    Our DPS team measures colloidal stability, for example by assessing second virial coefficient (A2, B22), and evaluating the parameter in relation to our experience and prior knowledge.

    Conformational stability refers to the stability of a given molecule with regard to its three-dimensional structure, as a function of stresses

    Our DPS team measures conformational stability using a panel of relevant endpoints, including melting temperature by differential scanning calorimetry using microcalorimeter (uDSC) and fluorscences and/or evaluating of higher order structure, e.g. by circular dichroism (CD) and/or fourier-transform infrared spectroscopy (FTIR).
  • Viscosity and rheological properties can impact manufacturability, and injectabiliy (administration), especially when administration volumes are somewhat limited, such as for subcutaneous or intravitreal use.

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