Preformulation and Formulation Development

Optimizing Conformational Stability and Biological ActivityMaintenance of the native three dimensional conformation is critical for the long term stability and biological activity of biotherapeutics. Biophysical characterization techniques such as circular dichroism, differential scanning calorimetry, FTIR, dynamic light scattering, and fluorescence spectroscopy provide a mechanism to assess the conformational and thermodynamic stability of proteins under a range of formulation conditions. These tools allow development scientists to differentiate various various buffer, pH, ionic strength, and excipient conditions, and identify the conditions that confer the optimum environment for the therapeutic protein.

Utilizing Advanced Statistical Design for Preformulation Development Preformulation development includes statistical design of experiments, allowing simultaneous evaluation of multiple factors and evaluation of interactions between factors. It is crucial to use advanced biophysical characterization techniques to evaluate the conformational stability of large molecules in addition to traditional methods for evaluation of chemical stability.

A large molecule preformulation development program typically includes the following activities:
Evaluate the effect of pH, buffer type, and ionic strength on solubility.
Evaluate the effect of various excipients on improving solubility if necessary.
Evaluate effects of pH, buffer type, and excipients on conformational stability.
Evaluate the effect of pH, buffers, excipients and ionic strength on physical and chemical stability.
Utilize a statistical design approach to identify the optimal conditions for structural, physical and chemical stability.
Perform forced degradation to elucidate product degradation pathways and to demonstrate the stability-indicating capacity of the analytical methods.
Forced degradation studies typically include restricted oxidation, deamidation, aggregation (via agitation), and / or acid / base hydrolysis.
Evaluation of heat stress, photo stress, and freeze thaw are also performed.

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Formulation Development for Numerous Dosage FormsFormulation development includes dosage forms for parenteral, oral topical and inhalation administration, including liquids, gels, suspensions, emulsions and lyophilized powders. Formulation scientists are highly skilled in the development of the dosage forms most relevant to biotherapeutics, with particular expertise in lyophilization and development of stable liquid formulations for proteins. High concentration antibody formulation development for subcutaneous administration requires particular emphasis on viscosity and tonicity. Lyophilization cycle development is performed in the context of the unique thermodynamic properties of the API to deliver an efficient, scalable, transferable process resulting in optimum product stability and reconfiguration characteristics. Formulation development capabilities also include:

Effect of excipients on solubility, tonicity, and viscosity Evaluation of antioxidant and conservative compatibility Container-closure compatibility Long term and accelerated stability studies.

Advantages of Formulation Development Approach. This outlined approach to preformulation and formulation development result in significant savings to the client by eliminating the variables associated with suboptimal formulations. Preclinical development efforts in PK, PD, ADME and toxicology occur with confidence that additional uncontrollable variables from unstable formulations are not introduced into the study. This benefit extends far into clinical trials as well, where assessment of toxicity, dosage levels and efficiency are substantially influenced by an optimal formulation that preserves the three dimensional conformation of the therapeutic protein. By eliminating uncontrolled stability variables, the focus is placed solely on the therapeutic performance and clinical outcome.