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8 Pharmaceutical Technology ® Trends in Formulation eBook September 2024 PharmTech.com Biologics vent-accessible surface area of the variable region of previously approved mAbs have been used to make predictions on aggregation, he notes. "If proteins can get re-engineered, then the Y TE mutations [M252Y/S254T/T256E] could be employed to achieve thermal stability," adds Lim, who explains that once a molecule passes the discovery phase, a for- mulation scientist would then need to analyze basic characteristics of the molecule to identify its distin- guished traits. "These analyses help us determine the onset temperature (T onset ) and melting point (T m ) of the molecules and provide us insight into how much the molecule can resist thermal stressors," he says. Furthermore, identif ying pH/ buffer levels is re- quired to earn both thermal and chemical stability, Lim adds. "We can also add various saccharide excip- ients to formulations, such as sucrose and trehalose, to further enhance thermal stability by about 2–3 de- grees Celsius. For sensitive/complex molecules [such as] antibody-drug conjugates, lyophilization may be the preferred technique to achieve maximum stabil- ity," he states. Meanwhile, other t y pes of nanopar ticles, such as polymeric ones, are being explored for thermal stability, says Ailhas. "Additionally, lyophilization combined with the appropriate selection of excipi- ents should be investigated to enhance the stability of temperature-sensitive products," she states. Unique excipients such as polyols, surfactants, amino acids, and antioxidants have been demonstrated to improve protein chemical stabilization and colloidal stability, Chrimes notes. "Beyond LNPs, other t y pe nanopar ticle carriers such as polymeric nanoparticles, silica nanoparti- cles, and gold nanoparticles are being investigated for the capability to stabilize the molecules through encapsulation," says Cao. Shifting focus: formulation to delivery mechanism At a certain point, once a formulation strategy is in place, focus shifts to the drug delivery method. Drug delivery systems are usually considered in later clin- ical stages of drug development, notes Lim, who em- phasizes that in early stages of drug development, getting a fast investigational new drug (IND) appli- cation approval is a high priority for drug developers. Speed in securing an IND approval grants a competi- tive edge to drug developers, especially in a drug dis- covery market that is dynamic. "The emphasis during the early stages is less on selecting a delivery system and more on obtaining reliable thermal and physical stability results for the targeted molecule," he says. Formulation development is usually initiated at the early stages of drug development as well, says Cao, who explains that early formulation development ensures the stability of the product and reduces the need for cold storage with, for example, techniques such as lyophilization. Formulations that result in stability can then inform the design of the delivery mechanism, he notes. "A study for delivery can also be conducted first to test which delivery method (intravenous [IV] bag, sub- cutaneous injection, etc.) is effective for the therapeu- tical drug, followed by formulation development," Cao also says. "Different modes of delivering the drug will require different drug concentrations. IV-bags do not require high concentrations of drug, but sub-cutane- ous does. Challenges and limitations observed in the delivery mechanism can drive further optimization of the formulation," he adds. "In my opinion," says Ailhas, "it is more beneficial to prioritize an optimized formulation that can func- tion in a non-cold environment. This approach sim- plifies production and storage, eliminating the need to find specific drug product manufacturers capable of handling cold manufacturing processes, which can be challenging to locate." Ailhas also points out that, although a formulation-first strategy may incur slightly higher costs at the beginning of a project, the long-term cost savings during the transition to good manufacturing practice manufacturing, either for clinical or commercial supply, will be significant. Chrimes agrees that is it important to prioritize a formulation-first strategy: "Optimizing the formu- lation to limit the impact of temperature excursions would be the preferred development path for biother- apeutics," he says, adding that every effort should be explored to limit potential liabilities as well as screen applicable excipients and explore presentations to "lock" the product in a stable state through techniques such as lyophilization, for example. Lyophilization removes water from sensitive products without dam- aging them. "Developing liquid formulations that are compatible with lyophilization can be an effective strategy for cost savings during clinical development where lyophilization cycles are deferred to commer- cial development," he states. LNPs are emerging as a formidable technology that can facilitate molecule stability in biologic- based medicines.