Formulation can make or break a development-stage protein drug, and add years of IP protection and value for post-patent molecules. Yet significant disagreement exists on the best time to undertake the formulation investment.
Robert E. Zoubek, Ph.D., head of protein characterization and preformulation at Formycon, a business unit of Scil Technology, advises customers to complete final formulation before Phase I.
He recognizes the dilemma of investing in formulation development before knowing if the drug will even make it to Phase II. “However, the reason many monoclonal antibodies fail is specifically because they are improperly formulated in the first place.”
Moreover, the moving-target approach to formulation, whereby tweaks are introduced over time, can be risky from a regulatory perspective. “Regulators have been known to ask for more tests on suboptimal formulations,” Dr. Zoubek notes.
“I know of one company that was asked to redo preclinical studies just as they were preparing to enter Phase II. Regulators wanted proof that the product as it was formulated at the time would not harm pregnant animals.”
He also cites ethical reasons for formulating from the start. It’s not right to subject Phase I subjects to a substandard formulation, he says, “just to save money.”
Dr. Zoubek believes the time for considering reformulation as a lifecycle-extending strategy depends on the therapeutic area and level of competition. Suboptimal formulations put companies at a competitive disadvantage, so it is never too early to consider reformulation.
However, all things being equal, companies need to factor in time-to-market, including any human studies that will be required. One and a half years before patent expiration is not too early, he says.
Sponsors should add time, possibly more than a year, when lifecycle extension includes more exotic, specialty-type extenders including nanoparticles, liposomes, and bioresorbable ceramics. These formulations will require more testing and more sophisticated analytics than straight-up liquid formulations. The same is true for lyophilization.
Since formulation development typically occurs during early clinical stages (or, optimally, even earlier)—when sponsors are scrambling to manufacture product for testing—material limitations can pose serious challenges. This is particularly true for products that will be formulated at high concentration.
High Throughput or "Rational"?
From his perspective as principal scientist at Cook Pharmica, Zachary Yim, Ph.D., is seeing more combination products than ever before, such as Fc fragments coupled with enzymes, small molecules, or peptides linked to proteins. “Formulation of these products is complex and multifaceted because you have to deal with both components.”
As a CMO/CRO, Cook sees formulation-development strategies of every type, duration, budget, and timeline. Dr. Yim says that formulation is often defined by when toxicology studies or clinical trial manufacturing must be completed. Cash-strapped sponsors do the best they can to meet minimal stability requirements.
“On the other hand,” says Dr. Yim, “those with more resources can think longer-term, because ideally you don’t want to change the formulation unless you have to.”
Whatever the strategy, many formulation developers today employ some type of design of experiment and high-throughput method to arrive at formulation candidates and, eventually, to select among and optimize these choices. Yet high-throughput methods can still take considerable time and always generate hundreds or thousands of formulations.
Dr. Yim suggests taking a tiered or stepwise approach that might begin with testing critical factors like pH or ionic strength, identifying optimized values and trouble spots, then tackling other conditions. “Doing a pH screen at the beginning could save a considerable amount of work.”
Then there is the issue of breadth vs. depth. When evaluating a very large number of conditions at once through high-throughput methods, it’s difficult to devote as much time per condition as, say, through a more rational or stepwise approach to formulation development.
“Detailed observation is often lost with robotics,” Dr. Yim explains. “Something can occur transiently and you miss it. It becomes a tradeoff. In addition, since all parameters are linked, you cannot change just one parameter at a time.”