Developing a stable formulation for a protein-based product is a critical step in the development cycle of a biopharmaceutical and will likely require significant resources and time. Over the years, Charles River has developed a number of protein formulations for different types of protein products and different routes of administration, including intravenous, intraperitoneal, intramuscular, subcutaneous and ocular. Our formulation team has the expertise and capabilities to work on complex formulations which, once developed, can be easily handed off to the manufacturing team of choice for scale-up.
The approach we take for protein formulation consists of first conducting a series of pre-formulation trials to establish product solubility in various pH conditions and ionic strengths and also their solubility in salts and other excipients which may include detergents and protein stabilizing agents. The choice of any detergents and other stabilizing agents is based on the protein hydrophobicity and secondary and tertiary structural characteristics of the protein. Once the solubility properties have been established, a new iteration of finely tuned pH conditions along with buffering agents, ionic strength and salts, plus the addition of stabilizing detergents and other excipients is conducted to obtain the needed product strength and stability at the desired storage temperature. To aid in selecting the optimal conditions in this latter formulation iteration, high-throughput stability screening is performed using proprietary formulation development techniques which use intrinsic and extrinsic fluorescence monitoring as a function of temperature modulation. Other stability-indicating screening techniques are then applied along with appropriately designed stress studies for final formulation selection. To minimize the number of iterations and study conditions, Charles River uses design of experiment (DOE) to screen through a vast number of potential excipients and identify optimal conditions resulting in maximum product stability. For ease of understanding, the various formulation steps described above are summarized in the following diagram.
We have developed proprietary screening techniques for rapid evaluation of a large number of excipients, and since these techniques allow for the interrogation of the secondary and tertiary structures of proteins, the obtained results are highly predictive of protein stability. As needed, we can easily and quickly develop new stability-indicating assays that are closely tailored to protein characteristics and attributes. Furthermore, since we are equipped with fully qualified stability chambers to address any stability storage requirements from -80 ºC up to 60 ºC with controlled humidity, as well as photostability, Charles River can support stability studies of formulated products not only under accelerated conditions but also for long-term storage conditions while adhering to cGMP requirements.