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18 BioPharm International eBook February 2020 www.biopharminternational.com states that lyophilization is under investigation as a means of stabiliz- ing viral gene therapy products, but that this work has been hampered by limitations in analytically deter- mining product potency during process development," she says. KNOWLEDGE AND SKILL Because biologics are generally not stable in aqueous formulations, storing them for long periods of time is diff ic ult and can com- promise their qualit y and ther- apeutic efficacy. Over the years, lyophilization has emerged as the preferential method for stabilizing these drugs because the process can preserve them in dry form. The complex structure and phys- iochemical properties of biolog- ica l-based molec u les, however, means that specialized knowledge and specialized skills are required to lyoph i l i z e t he m. C ho osi ng the right CDMO partner for lyo- ph ili zat ion ser v ices w ill mea n evaluating not just their equip- ment, but their k nowledge and skill set on handling biologics. Specialized knowledge includes having the understanding of how commonly used components in biomanufacturing formulas can act during the freeze-drying pro- cess. Common components such as buffers and surfactants used in the manufacture and formulation of proteins, antibodies, and other biologics can destabilize molecules in freeze-dried, or even frozen, for- mulations or may contain com- ponents that precipitate during freezing, for example (6). Further, each biologic product requires a lyophilization process designed specifically for that mol- ecule. This may entail extensive study of the specific molecule's properties to understand the freez- ing and drying behavior of the components used in the formula- tion of the final product. Studies should also be conducted to deter- mine how factors such as formula- tion strength and container type affect the lyophilization process. In some cases, biologics are formu- lated with complex components such as nanoparticles, microparti- cles, and liposomes (7). These also require study, or at least sufficient knowledge, to understand their behav ior dur ing the f reeze- dr y process. Lyophilization of biologics is also challenged by the sensitivity of these molecules. Biologic mole- cules can interact at the air/liquid interface, the liquid/primary pack- aging interface, or at the solution/ ice interface where protein unfold- ing can occur, resulting in aggre- gration and loss of bioactivity. In addition, lyophilization threatens the stability of protein structure when water is removed dur ing the process, which compromises the biologic molecule's bioactiv- ity. Bioactivity is dependent on the molecule's interaction with sur- rounding water. Therefore, there must be some residual moisture retained in the final lyophilized cake to ensure stability, but under- s t a nd i n g how mu c h r e s id u a l moisture should remain is key for proper lyophilization (8,9). "To develop a manufacturing process for a biologic product— i nc lud i ng lyoph i l i z at ion c yc le development—requires an under- standing of the product failure modes and assessment of product stability," says Saffell-Clemmer. In contrast to small molecules, char- acterization of biologic product sta- bility requires multiple orthogonal methods for common degradation modes, such as deamidation, oxi- dation, and aggregation, she notes. "A lyophilization service must be resourced with bioanalytical scien- tists experienced in the analysis of proteins and monoclonal antibod- ies using methods such as chro- matography, mass spectrometry, capillary electrophoresis, and light scattering," she adds. Un d e r s t a n d i n g t h e t e c h n i - cal principles of lyophilization is another important aspect. "The pro ce ss of lyoph i l i z at ion i s a lengthy operation in which prod- uct vials are held partially stop- pered for time periods of hours to days. By the nature of its long duration in comparison to other unit operations in the filling pro- cess, it presents the greatest risk of failure, which can have signif- icant financial consequences for high-cost, difficult-to-manufacture dr ug substances," notes Saffell- Clemmer. "A knowledgeable and skilled outsourcing partner can reduce this risk through intelligent lyophilization development using a design space." Saffell-Clemmer adds that using design space in cycle development Partnerships for Outsourcing Manufacturing It is estimated that the market for lyophilization services for biopharmaceuticals will grow by 9.5% annually between 2017 and 2027. Each biologic product requires a lyophilization process designed specifically for that molecule.