Formulation Development

KBI’s approach to formulation development is based on the strategic pairing of two complementary scientific disciplines:

• Establishing a comprehensive understanding of the thermal, physical, chemical, and conformational stability of the protein.
• Employing statistical design-of-experiment (DOE) to evaluate main effects and interactions effects on protein stability

Together, these techniques enable KBI to develop robust formulations by eliminating uncontrolled stability variables, thus placing the focus solely on therapeutic performance and clinical outcome and results 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 uncontrolled 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 efficacy are profoundly influenced by an optimal formulation that conserves the three dimensional conformation of the therapeutic protein. KBI’s data-driven approach can also strengthen responses to regulatory inquiries.

The KBI team has completed more than 80 successful protein, peptide, and vaccine formulation development programs. Liquid, lyophilized, and suspension formulations developed by KBI have been successfully transferred to many fill/finish CMO’s and utilized for the manufacture of clinical and commercial drug product for parenteral administration (IV infusion, IV push, SC, IM).

Our Approach: Formulation Development Process

KBI’s approach to formulation development is based on first establishing a comprehensive understanding of the thermal, physical, chemical, and conformational stability of the protein. We then leverage this initial design space to develop a formulation and process which is tailored to the unique structural aspects of the protein, so as to maintain its native three-dimensional conformation to the greatest extent possible throughout the manufacturing process and in the final dosage form. We rely heavily on statistical DOE to evaluate main effects and interactions effects on protein stability. We perform forced degradation and accelerated stability studies to assess suitability of formulation conditions.

Optimizing Conformational Stability & Biological Activity

Maintenance 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, dynamic light scattering, FTIR, and fluorescence spectroscopy provide a mechanism to assess the conformational, physical, and thermal stability of proteins under a range of formulation conditions.

These tools allow KBI Biopharma to differentiate among various buffer, pH, ionic strength, and excipient conditions, and identify the conditions that confer the optimal environment for the therapeutic protein.

Utilizing Advanced Statistical Design for Preformulation Development

KBI Biopharma’s approach to preformulation development relies on statistical design of experiments, allowing for simultaneous evaluation of multiple factors and interactions between factors – thus saving valuable time and resources.

A large molecule preformulation development program at KBI Biopharma 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 capability of the analytical methods

Forced degradation studies typically include forced oxidation, deamidation, aggregation (via agitation), and/or acid/base hydrolysis. Evaluation of heat stress, photo stress, and freeze thaw are also performed.

Liquid & Lyophilized Pharmaceutical Formulation Development

Formulation development capabilities at KBI Biopharma are focused on the parenteral dosage forms most relevant to biotherapeutics, with substantial expertise in liquid and lyophilized formulations. KBI has successfully developed stable liquid formulations at protein concentrations ranging from >1mg/mL to 200mg/mL.

Lyophilization cycle development is performed in the context of the unique thermodynamic properties of the API to deliver an efficient, scaleable, transferable process resulting in optimal product stability and reconstitution characteristics.

KBI Pharmaceutical Formulation Development Services Include:

• Effect of excipients on solubility, tonicity, and viscosity
• Evaluation of antioxidant and preservative compatibility
• Manufacturing feasibility via TFF and filter compatibility
• Syringeability and Container-closure compatibility
• Long term and accelerated stability studies