This article is part of a special issue on API Development, Formulation, Synthesis and Manufacturing.
Resource allocationThe crux of the fit-for-purpose model comes out of a concept of "cost-disciplined science," says Mark Powell, senior vice-president of pharmaceutical development at Bristol-Myers Squibb. "Cost-disciplined science is a development strategy that we are applying throughout R&D," he says. "But in the specific context of drug development, this concept is based on maximizing overall productivity by selectively allocating resources to compounds based on where they are in the drug-development continuum. Among pharmaceutical companies as a whole, we know that there is a high level of attrition of drug candidates as they proceed through the drug-development process. So how do we allocate our resources in the best way to focus on the right drug candidates, and what is the best way to apply our resources so that the most promising candidates have the best chance to succeed?"
The fit-for-purpose model at work
To address that issue, Bristol-Myers Squibb implemented a fit-for-purpose model for early-stage compounds. Under this approach, the company reduces the level of process optimization early in development for both the drug substance and drug product (i.e., formulation). Historically, the company's chemical development department invested significant resources in synthetic process optimization prior to producing early active pharmaceutical ingredients (APIs) batched for clinical studies. In the new fit-for-purpose model, process optimization is generally delayed until a compound proceeds beyond Phase I and approaches or achieves proof of concept. Using this approach, the company liberates resources that can be applied to additional early-stage compounds or can be applied later in development after a compound has been shown to be a viable drug candidate from a clinical perspective. Often the company will elect to outsource the manufacturing of the smaller quantities of the API needed at this early stage (i.e., Phase I) using the discovery-chemistry route that was developed internally. If a molecular target is of particular interest or priority to the company, process optimization can begin internally in parallel to the outsourced early API manufacturing work, but that is reserved for only the highest priority programs, Powell says.
Bristol-Myers Squibb applies a similar philosophy in formulation development by using a de minimis approach to the development of dosage forms that will be used in early clinical testing. Historically, tablet or capsule formulations were developed prior to the start of Phase I clinical trials. Given the wide dosing ranges employed in these early clinical studies, the formulation development work was significant and time-consuming as well as API-consuming. Approximately 70% of all the early API manufactured was used for this formulation-development work. The new fit-for-purpose formulation approach has significantly changed that.
The company predominantly uses a "powder-in-a-bottle" formulation approach in which it puts the API directly in a bottle and makes a simple solution or suspension for drug administration in Phase I clinical studies. Applying this approach requires several additional factors to be taken into consideration for a Phase I clinical trial, says Powell. For example, a pharmacist has to be physically present at the clinical-trial site to make up the final dosing solution. The on-site pharmacist requirement can be an additional cost and also may limit clinical-site locations for a given trial.
By minimizing formulation development, vital resources are freed to support additional early-stage projects, and/or focus on the highest priority projects. Additionally, early clinical projects proceed at a much faster rate, thereby reaching critical decision points earlier. Bristol-Myers Squibb may elect to do more advanced formulation development for a given early-stage compound if it feels that it is necessary, but that decision is made on a case-by-case basis and is reserved for the highest priority programs or compounds.