Is The API In Capsule Method Overshadowing The Science Of Formulation Development?

By Todd Daviau, Ph.D.

In today’s market, pharmaceutical and biotech companies are being asked to do more with less. Diminishing resources, pipelines, competition, and increased regulatory hurdles are forcing us to rethink our strategy. We must work smarter, not harder. The adage “time is money” is a fact well-understood by those in the pharmaceutical industry, where developing a new product can take almost a decade and cost hundreds of millions of dollars. To maximize patent life and remain competitive, small biotech companies, as well as large pharma, must avoid costly and time-consuming product development.

In early Phase 1 cases, many will find themselves choosing to deliver the neat drug substance or API directly (e.g. API in a capsule or bottle). This pathway offers an appealing alternative, as it allows companies to obtain critical clinical trial data before the added expense of formulation development and, in particular, excipient compatibility and process optimization experiments. Saving time and money is the ultimate driver in many cases. However, one must not overlook the science, possibly resulting in loss of time, as well as additional developmental costs.

In a day and age where critical “go/no-go” and long-term development decisions are based on early success in order to receive follow-on tranches of venture capital financing, it should come as no surprise that limited financial resources are forcing pharmaceutical companies to take shortcuts wherever possible. In other words, decisions regarding the fate of new chemical entities are, more often than not, based on the bottom line.

Understand the dilemma — not wanting to be the “decision bottleneck,” pharmaceutical development teams often implement API in capsule approaches to meet aggressive Phase 1 clinical study start dates. To make it an easier decision, precision equipment has been introduced that can accurately fill hard gelatin capsules or vials with neat drug substance quickly and efficiently. But has this approach become overused, with aggressive timelines and cost containment overshadowing the science of formulation development?

The fact is, API in capsule/bottle approaches for early clinical studies may defer, but will not eliminate, the need to conduct formulation development and process optimization. It is therefore critical to weigh carefully the impact on the overall development plan (as well as cost and time) of using neat drug substance-filled capsules/vials versus a formulated product in early studies.

Neat dosing of drug substance can result in greater total development costs.
Since the API in bottle/capsule approach only defers the downstream pharmaceutical development work needed to supply later phase clinical and commercial product, it is additive to the total development costs. The added costs are typically minor when taken in context of a typical development program, but should be recognized as not providing a formulation “free ride” through development.

Neat dosing of drug substance may result in greater total development time.
Because excipients and other downstream manufacturing processes may alter the drug’s pharmacokinetics and oral bioavailability, formulation decisions based on neat API in capsule projects may cause decisions to be made that detrimentally affect downstream development. This may lead to added time and the need for additional excipient compatibility studies or additional bioavailability studies during critical downstream development.

Not all APIs are suitable candidates for neat dosing into capsules.
Because of the absence of a tamping mechanism on most API in capsule machines, the actual amount of powder that will fit in a capsule may be limited by the powder’s physical characteristics. In some cases, neat drug substances may require preprocessing to increase density and enable high-dose API in capsule. High-dose capsule filling also poses challenges because of the inability to use material bulk density to accurately predict allowable capsule fill weights. The allowable fill weight in a particular capsule size depends on the material’s physical characteristics, which may be limited by the instrument’s filling mechanism.

Excipient compatibility studies should be done with capsule material anyway.
Since excipient compatibility studies should be performed between the API and the capsule material, it only makes sense to begin excipient compatibility studies as early in the process as possible. A carefully designed excipient compatibility matrix should not take any more time on stability than that of API and capsule material(s). Added costs, of course, would be a result of the additional analytical time.

Not all drugs are suitable candidates for neat dosing of drug substance.
Before contemplating an API in bottle/capsule project, it is imperative that physicochemical properties of the drug substance be evaluated. Drugs with inadequate or limited bioavailability may require formulation intervention to achieve adequate bioavailability and/or improve adsorption kinetics. In addition, an increase in drug bioavailability due to formulation can significantly decrease the quantity of drug substance required to supply clinical studies. Since the supply of drug substance can often be rate-limiting in the initiation of early clinical studies, removing this drug substance bottleneck can actually decrease the time requirement to enter larger studies and significantly reduce program costs for drugs with complex and expensive manufacturing processes.
In the world of contract pharmaceutical R&D, success hinges on two things: quality and timeliness. More often than not, the two are inextricably connected. However, in the final analysis, the strategic decisions tied to pharmaceutical development become ever more complex as the business, regulatory, and scientific demands escalate. The manufacturing of early clinical supplies by dispensing of neat drug substance into capsules or vials may provide an attractive approach to shorten the time for acquiring essential clinical data. However, the downstream implications for later stage development must be carefully weighed, in light of the total development picture.

About The Author
Todd Daviau, Ph.D., is the CEO of CoreRx, a contract pharmaceutical development organization, providing a complete spectrum of cGMP solutions for pharmaceutical dosage form development and CTM (clinical trial material) manufacturing. Daviau has more than 25 years of pharmaceutical CMC experience, from drug discovery, R&D, through product launch.