Next to the active ingredient, formulation is arguably the most critical component of a biopharmaceutical product. Formulation scientists from leading biopharmaceutical companies, vendor firms, and universities will be discussing challenges in the field and sharing tips on overcoming those obstacles at the IBC conference “Formulation Strategies for Protein Therapeutics” to be held in Raleigh, NC, next month.
Dosage form elements, especially formulations, can evolve as products undergo clinical testing. Angela Kantor, principal research scientist at Wyeth, uses a Cheshire Cat analogy. When Alice asked the Cat which way she should go, the feline hedged: “Well that depends a good deal on where you want to get to.”
The same applies to formulation strategies, Kantor says. “It’s all about decisions. Formulation strategies have to be based on goals, on destinations. Not every biological belongs in, say, a needle-free device for home administration. Along the way, you have to make sure you’re doing the right thing for the patient and the product. You need a strategy for arriving at a good product, and how you get there matters.”
A life cycle focused formulation strategy will better position the product for a competitive future and define, at every point on the development continuum, where the product is going.
One critical period along that continuum is clinical testing. In 2006, Wyeth adopted the Learn & Confirm clinical development paradigm, a flexible approach that differs from conventional Phase I–III trials. The Learn phase is geared toward understanding a drug early in clinical development, before committing resources to a confirmatory Phase III trial.
To achieve this, testing is initiated in representative patient populations rather than in normal human subjects. This adaptive trial design permits an earlier assessment of efficacy. “While doing safety and tolerability studies, you’re also getting an earlier read on efficacy, so when you enter late-stage trials you know more than you would have after conventional Phase I/II studies.”
Learn & Confirm has the potential to compress clinical development and guide the life-cycle formulation strategy, since it provides earlier insights into maximizing Wyeth’s five points in the product life cycle: safety, efficacy, tolerability, convenience, and affordability. “These are our destinations,” Kantor notes, “and as formulators, our goal is to maximize these for the patient while delivering a product that maintains value throughout its life cycle.”
Because drug development is risky business, the formulation strategy must be based on clinical and marketing knowledge gained during development, and the earlier this occurs, the better. “That’s where the Learn & Confirm paradigm could give us an edge,” Kantor notes. “Making too much of an investment before knowing if a drug will be successful diverts resources that could have been used to develop other promising candidates. The risk is investing too much, too soon.”
For example, manufacturers often prepare biologicals in lyophilized form because that is the easiest way to get them into Phase I although it may not be the ideal market formulation. A liquid may be more attractive because of convenience or cost, and convenience is preeminent; developers might even consider an auto-injector or needle-free device.
“As you learn more about a drug, reformulation is a life-cycle change that may be desirable to achieve better storage, stability, or performance—things you always want to improve.”
Particularly for biologicals, life-cycle considerations should focus on making parenteral administration more palatable. “Nobody likes injections. But if we can make them more convenient, less frightening, administer them less frequently, or make them less expensive, then we’ve made a better drug.”
Earlier Is Better
Applying analytical methods early on in development can help scientists anticipate and mitigate formulation problems that arise later on. This is the key message of Robert Simler, Ph.D., staff scientist at Genzyme. Dr. Simler applies conventional methods like differential scanning calorimetry, light-scattering, size-exclusion chromatography, and analytical ultracentrifugation, as well as spectrometric techniques like circular dichroism, fluorescence, and FTIR to preformulation projects with the idea of establishing methods as early as possible.
The techniques themselves are not extraordinary, but the point at which they are applied and worked out is. Once the methods are in place, Genzyme scientists can draw on them for quality control and stability studies, during clinical development and beyond. “We use those techniques, early on, to identify potential problems, or to get better characterization at the front end of development rather than waiting and reacting to what happens down the road.”
Obtaining formulation information early requires communication between groups to determine the most appropriate techniques. The two principal hurdles at this stage are material availability and time lines. Preclinical-stage biologicals are in short supply because production batches are small while demands for animal testing are substantial. “You can’t do everything,” Dr. Simler observes. “Animal testing chews up a lot of material, as do analytics.” The time constraint, particularly getting through preclinical studies as rapidly as possible, is common to all pharmaceutical development, but especially acute for biopharma.
“But when the analytical work is successful, and you’ve identified a protein’s main stability issues, and you have the techniques lined up, you have powerful tools to move forward with, as the molecule is being developed,” Dr. Simler adds.
One technical hurdle to overcome, he says, is particulate testing. “There’s a mandate from FDA to look closely at this.” Since every biomolecule is unique, even within a class, a one-size-fits-all approach works as poorly for particulates as it does for formulations. Genzyme has been experimenting with instrumentation to characterize particulates, and works closely with vendors to improve and fine-tune those products.