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Batch-to-batch variability and impurities present critical challenges.
Many drug molecules, particularly biologics and vaccines, are unstable at room temperature when formulated in aqueous solutions and must be frozen or lyophilized (freeze-dried) to allow their storage and shipment. Freezing and freeze-drying involve harsh conditions that can degrade the active ingredients. Cryoprotectants and lyoprotectants are excipients used in drug product formulations to ensure that safe and efficacious products are obtained following these processes. As such, the quality of those excipients can have a direct impact on the final stability and performance of frozen and lyophilized drugs and vaccines, as explained independently by two industry experts.
Excipients used as cryoprotectants and lyoprotectants serve mainly to protect the drug substance in a formulation from degradation or disassociation during the freezing or freeze-drying process, according to Christy Eatmon, global subject matter expert, sterile drug products, in the pharma services business of Thermo Fisher Scientific. Lyoprotectants also provide a bulking effect so that the resulting dried cakes can be readily reconstituted.
Most cryoprotectants are monosaccharides (sugars), polysaccharides, or polyols, observes Virginie Le Brun, associate director of formulation development for Lonza Drug Product Services. There are limited options, she adds, because only certain excipients are suitable for use in drugs for human use, particular
The selection of the best excipient or combination of materials and their quantity(ies) is dependent on the molecule type, according to Eatmon. She recommends the use of a design-of-experiment (DoE) approach to identify which materials work best with the target drug product.
Ideally, formulation compositions for drug products that must be frozen or lyophilized should be kept simple. “Whenever possible, just one excipient with sufficient ability to protect, and if necessary act as a bulking agent, should be selected,” Le Brun says. However, she adds that there might be situations where a combination is needed to achieve the most stable formulation conditions.
During formulation development, it is important, observes Heiko Nalenz, associate director of process development for Lonza Drug Product Services, to take a structured approach to development, addressing process challenges during early formulation selection. “Excipient selection should be based on the intended storage conditions and/or compatibility with the freeze-drying process. For this purpose, the thermally induced transitions of the complete product matrix (e.g., glass-transition temperature and collapse temperature) should be characterized,” he explains.
Eatmon agrees, once again underscoring the value of performing selective DoE studies to determine which excipients are most successful for the formulation and product under evaluation. “Characterization is important to understand and develop key parameters of the lyophilization cycle. For example, with a small molecule, it is important to understand whether the molecule is crystalline or amorphous. With that information in hand, the eutectic point or glass-transition temperature should be determined to enable excipient selection,” she comments.In the case of large molecules or more complex formulations, such as dispersions, Eatmon notes that the need for a combination of excipients is more likely.
As with APIs, the quality and purity of lyo/cryoprotectants used in formulations that are frozen or lyophilized is important. “Impurities in materials may cause slight differences in critical attributes, which can lead to incomplete freezing or poor sublimation during the drying process,” Eatmon says. They may also negatively affect the product’s stability in the frozen or freeze-dried state, according to Nalenz. For crystallizing excipients, he points to the potential of varying impurity profiles to increase or decrease their propensity to crystallize, which might impact the quality of the drug component if it ends up in the final product in a non-desirable state.
The biggest potential impact of poor-quality cryo/lyo excipients is, according to Eatmon, for the resulting frozen or lyophilized product to fail to meet acceptance criteria, resulting in rejection of the material. “Robust quality systems should prevent the use of non-compliant materials, but if the quality issue is unexpected, timelines may be delayed while a replacement is sourced. Plans should be in place in advance to efficiently manage this type of scenario,” Eatmon emphasizes.
In addition, variability in the properties of excipients can also create challenges. “Even excipients in compliance with compendial quality specifications may have some variability in their properties or impurity profiles that may impact cryo/lyoprotective properties,” Nalenz remarks. This variability for many cryo/lyoprotectants can be attributed to the fact that they come from plant sources (e.g., starch), according to Le Brun.
Suppliers can help avoid such issues by deeply characterizing the cryo/lyo excipients they produce and obtaining knowledge of how variability might impact their products’ cryo-protective and other properties, observes Nalenz. Drug manufacturers, meanwhile, can for lyophilized products perform lyo cycle tests using different lots of lyoprotectants to ensure that batch-to-batch variability is accounted for in the final formulation, according to Eatmon. She also recommends that conservative measures be taken when developing lyophilization cycles to account for some variability in excipients, upstream drug substances, and drug-product manufacturing processes.
Appropriate sourcing of any type of excipient is essential to ensuring security of supply and the use of high-quality, compliant materials. For instance, Eatmon stresses the importance of sourcing materials that are intended for pharmaceutical use rather than nutraceutical- or food-grade materials. She also indicates that excipients classified as ultra-pure or low bioburden are preferable for use in injectable products, which comprises most frozen and freeze-dried products. In addition, given the potential for variability in excipient batches, Le Brun emphasizes the importance for formulators of understanding that variability and its impact on the properties of the drug product before selecting a specific excipient supplier.
While common cryo/lyoprotectants and bulking agents are well understood, used in a variety of commercial products, have multiple high-quality sources, and comply with a variety of compendia, there are limited
numbers of them suitable for parenteral applications, according to Eatmon. Other than the challenges related to impurities and variability, Le Brun comments that the limited options can represent a significant hurdle, particularly for newer modalities.
It is hoped that the FDA’s Pilot Program for the Review of Innovation and Modernization of Excipients (referred to as PRIME), which was launched in September 2021 (1), will lead to a regulatory pathway for approval of novel excipients and innovation in the excipients space, including new cryo- and lyoprotectants.
Cynthia A. Challener, PhD, is a contributing edtior to Pharmaceutical Technology.