This article is part of a special issue on API Development, Formulation, Synthesis and Manufacturing.
Pharmaceutical companies face the ongoing challenge of how to best allocate research and development (R&D) resources to make
the drug-development process work in the most time efficient and cost-effective way. Industry estimates put the average time
to develop a drug at 10–15 years at an average cost of $1.2–1.3 billion (1). As a result, pharmaceutical companies have to
consider new ways to make the process work better in an overall economic environment of declining budgets and tighter resource
allocation. Such is the case for Bristol-Myers Squibb (New York), which implemented a "fit-for-purpose" model for how the
company develops and produces clinical- trial materials for early-stage drug development.
(ELLIOT ELLIOT, GETTY IMAGES)
The 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.