Timing, thoroughness, simplicity, and knowledge are critical components of formulations, particularly with respect to the ongoing analytical work conducted during preclinical and clinical development.
While small molecule drugs rarely fail due to formulation problems, the same cannot be said for biopharmaceuticals. The cytokine fusion protein mentioned above would not have been approved had it not been reformulated in a lyophilized form. Stability failures can occur as late as Phase II, after tens of millions of dollars have been invested, and the prospect of re-formulating is a costly one.
With formulation, the more effort invested up front the better. Establishing analyses appropriate to both formulation and stability-determining assays before entering human studies is ideal since these drugs are unlikely to experience formulation-related issues. The most efficient way to do this is to perform a formulation matrix construction and develop assays to circumvent interference from excipients.
A thorough understanding of one’s biological agent, route of administration, and pharmacokinetics is indispensible for a successful formulation program. Within that framework, the aim is to arrive at the simplest formulation that satisfies requirements of stability, activity/potency, and analytics. This is not always easy to achieve as formulations might contain excipients that are suitable for use in the laboratory but not for use in humans, that interfere with common analytical methods, or that do not support long-term stability studies.
It is no exaggeration to say that for practical purposes formulation carries approximately the same significance for the commercial success of a biopharmaceutical as the drug substance itself.