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6 Pharmaceutical Technology ® Trends in Formulation eBook September 2024 PharmTech.com Biologics manufacturing impurities should also be considered during formulation development." Heonchang Lim, director, Formulation Develop- ment, Samsung Biologics, agrees that finding the ideal range of pH and buffer conditions while select- ing the optimal formulation condition to get a good thermal stability property are primary factors that challenge formulation development in these mole- cules. However, he notes, the thermal stability prob- lem can mostly be solved by using optimal pH buffer and excipient combination. "Nowadays, we bump into another challenge to de- velop an optimal formulation condition. That is re- garding solubility and hydrophobicity of the molecule. Though clients would prefer higher concentrations, when taking unique characteristics of molecules into consideration, formulation scientists cannot always get high enough concentrations. In addition, pH shift may occur due to the Donnan effect," Lim says. "Consequently, when a client requests a highly concentrated formulation, particularly above 100 mg/mL, [the] formulation team at Samsung Biolog- ics implements rigorous gate checks to prevent such challenges from arising during formulation stages." Meanwhile, Caroline Ailhas, Pharmaceutical De- velopment director, CARBOGEN AMCIS says that, for her, the main factors challenging formulation devel- opment for temperature-sensitive molecules revolve around maintaining the structure and functionality of the molecule and defining the required duration of stabilization. The latter can vary from a few days—to allow for manufacturing and visual inspection be- fore storage at 2–8 °C—to several months, or even years. "The definition of this duration significantly impacts the formulation strategy," Ailhas says. "One of t he key performance indicators for t he development of biotherapeutic formulations is col- loidal stability to prevent protein aggregation and potentially precipitation," Greg Chrimes, site head and vice-president, Analytical and Formulation Sci- ence, KBI Biopharma, adds. He points out that pro- teins may denature and aggregate at interfaces such as air/liquid, liquid/liquid, and liquid/solid. Chem- ical modifications and degradation may also impact effector function, efficacy, conformational stability, and other important parameters, he emphasizes. "Excipients are evaluated during formulation devel- opment to limit product denaturation that may lead to particle formulation or chemical modification. Those may include buffering components, polyols, surfactants, amino acids, and antioxidants, to name a few. Finding the optimal combination components requires a methodical approach with matched ana- lytics such as differential scanning calorimetry (DSC), dynamic light scattering (DLS), dif ferential scan- ning f luorometry (DSF), and other product-specific techniques to down-select to a final formulation," Chrimes states. Innovations targeting stability Lipid nanoparticles (LNPs) are emerging as a formi- dable technology that can facilitate molecule stabil- ity in biologic-based medicines. "LNPs facilitate the stabilization of the molecule due to their amphiphilic nature. This property allows large molecules to main- tain their structure by interacting with either the polar head of the lipid or with the hydrophobic part of the lipid," says Ailhas. Ailhas also points out that the variety of available lipids offers numerous options for LNP composition and stabilization strategies. Because of this variety, LNPs composed of different lipids are highly versatile, enabling them to stabilize various molecules, such as peptides or nucleic acids, with different charges. Because LNPs can be used to encapsulate biother- apeutics, they protect the fragility of these therapies from accelerated degradation in vivo, Chrimes says. He explains that LNPs are biocompatible and natu- rally break down; however, the biodegradation needs to be timed to allow mRNA (as one example) to enter the target cells. "This type of delivery platform has accelerated the use of mRNA therapies. The control of lipid impurities generated during production of LNPs has also been reported to improve shelf life," he adds. L NP encapsu lat ion sh ields molecu les, such as mRNA, from temperature change, oxidation, and enzymatic degradation, Cao states. However, formu- lation development for mRNA-based therapies will still face the same challenges as mAb formulation development, Cao notes. "LNPs require different ra- tios of lipid components, such as ionizable lipids, PEG [polyethylene glycol]-lipids, cholesterol, and phos- pholipids, for their stability," he emphasizes. In addition to LNP technology, protein engineering and lyophilization are other techniques employed to facilitate the development of formulations that can offer better stability for temperature-sensitive mol- ecules. "Development of stable products at ambient temperature is typically the preferred endpoint for biopharmaceutical formulations. However, it is not of ten obtained due to t he physica l forces experi- enced during transport, storage, and delivery," says Chrimes. He explains that product liabilities can be removed in the primary sequence of a biotherapeutic, in some cases to eliminate the instability. He points to lyophilization as an often-successful technique to avoid colloidal instabilities that occur during ship- ment or long-term liquid storage. Protein engineering and the use of machine learn- ing, meanwhile, has been increasingly used to de- velop m Abs that are more thermostable, says Cao. Furthermore, the use of AI to analyze the local sol-