Preformulation Reduces The Risk Of Drug Failure

By Cindy Dubin, Contributing Writer

When Millennium Pharmaceuticals wanted to find a formulation that would alter the biodistribution of an oncology agent, it turned to Particle Sciences, Inc. (PSI), a CRO, to perform the development. But, if not for the preformulation work that Millennium performed up front on its own, augmented by PSI’s preformulation, finding the right formulation would have been a more time- and cost-consuming process. “Preformulation enabled us to find the right dosage form that would overcome the toxicity issue we were having,” says Michael Kaufman, Ph.D., VP of pharmaceutical sciences at Millennium: The Takeda Oncology Company. Kaufman was a panelist at the Drug Delivery Partnerships (DDP) conference this year, discussing how preformulation is the new formulation.

Preformulation is an important development step used to understand the challenges that a particular compound may pose. The panel describes this step as a bridge between discovery and development, where the physical and chemical characteristics of a new molecular entity (NME) are determined through solubility, dissolution, and physiochemical studies in an effort to better understand the molecule. Initial compatibility studies with excipients also can be performed during preformulation.

Preformulation Overcomes Compound Challenges
“Getting this data earlier in the development process enables formulators to make more informed dosage form decisions,” says Robert Lee, Ph.D., VP of pharmaceutical development and quality at PSI and a member of the DDP panel. Preformulation is not a new stage of development, but can be defined differently by different companies. The panelists agree that preformulation brings formulation teams into the development process earlier. At Eisai Pharmaceuticals, for example, the formulation group gets involved when issues arise with difficult-to-deliver compounds. “Recently, we have worked with our discovery teams on low-solubility compounds to enable dosing in animal models at the precandidate selection stage,” explains Geoffrey Hird, Ph.D., principal scientist, formulation and drug delivery technologies at Eisai, and a member of the discussion group. “Our involvement has allowed the discovery teams to rapidly screen promising compounds and develop preclinical formulations that overcome compound challenges.”

At Millennium, the challenge was related to toxicity. It was found during early preformulation that upon delivery in animal studies, the oncology agent was localizing in the liver more than in the tumor. Kaufman believed it was critical to bring the PSI formulation team into the fold to help overcome this obstacle.

Millennium provided PSI with the drug and physiochemical information obtained during the preformulation work to help PSI scientists determine which of many formulation approaches would enable the active pharmaceutical ingredient (API) to bypass the liver and target the tumor. Kaufman says that eventually two formulation approaches presented the most favorable delivery options and were tested. Ultimately, it was PSI’s nanoparticle approach that had the most pronounced results in mice for delivering the drug to the tumor and sparing the liver. “Our up-front preformulation work helped to quickly narrow the formulation search and weed out the formulations that wouldn’t work for intravenous drug delivery,” says Kaufman.

While Millennium is still contemplating its next step in relation to the PSI formulation, Kaufman says that combining the preformulation data with PSI’s formulation produced the correct measured amount of drug to avoid organ toxicity. This knowledge can be applied to develop a final dosage form (i.e. tablet, capsule, parenteral) that meets the needs of patients and caregivers.

While preformulation data may support a compound moving forward to formulation development, in other cases, it may become apparent from the data that it may be difficult to develop a suitable final dosage form (i.e. due to low permeability and high required dose). At that point, the team may choose to synthesize a new molecule, or other formulation technologies may be required.

“If you don’t understand the compound, it’s hard to design appropriate dosage forms for the best chance of success,” says Lee. “You might get lucky if you happen upon your dosage approach by chance, but the best approach is through methodical, systematic preformulation.”

Preformulation Can Save $500,000
By having formulators interact with discovery organizations at an earlier stage, the benefits of formulation and drug delivery technologies are being realized earlier for compounds going through the discovery process. Hird says some of these benefits of early formulation interaction with the discovery organization are:

• applying drug delivery technologies, such as solubilization technologies, to in vivo compound activity screening studies
• increasing administered doses to support toxicology studies
• improving the transition between the discovery and development organizations
• incorporating pharmaceutics and drug delivery technology input into candidate selection.  

“Earlier interactions between the discovery, preformulation, and formulation teams can help to speed development timelines and clinical trial entry by applying formulation and drug delivery technologies to challenges faced during the development process,” says Hird. “If, during preformulation, a decision is made to use enabling formulation technologies, the earlier the technologies are implemented and used in discovery and toxicology studies, the sooner the drug can enter the clinic.”

The panel agrees that most drugs do go on to clinical testing if preformulation is performed. The panel also agrees that companies that do not perform preformulation run the risk of drug failure.

According to Hird, companies have to do some sort of preformulation in order to understand the molecule enough to formulate it. “I think that having good interaction between preformulation and formulation at an earlier stage in development helps to increase a chance of a drug making it to the clinic.”

For those companies that prefer not to take the risk and perform preformulation, they can expect to add a couple of months to the development time line at the outset, but time is saved in the long run because the number of false starts (formulation development studies that result in a drug product that is unstable, poorly dissolving, or otherwise does not meet requirements) is reduced. For instance, says Kaufman, if preformulation studies show that a new drug is unstable at high humidity, then the formulation group can quickly select moisture-resistant packaging without having to perform extensive stability studies.

Preformulation can also save a significant amount of money. According to Kaufman, each time a formulation is tested, a portion of the API is used. If preformulation is performed, and there is a good understanding of the compound, this helps sift through a myriad of formulation options. Thus, less API will have to be used.

“Let me put it in numerical figures. Using just one kilogram of an API can cost $100,000 at the early stage of development,” explains Kaufman. “Through preformulation, we can theoretically save 5 kilograms of API. Saving time and money. What more is there?”