Design of experiments (DOE) is a valuable tool for identifying aspects of a formulation that are critical to product quality. The formulation design space can be characterized by performing excipient robustness studies that use DOE. This paper presents considerations for performing robustness studies as well as two case studies in which DOE was used to determine the robustness of protein formulations to changes in protein, excipient, and pH levels. The results from the DOE studies identified formulation components that must be tightly controlled and showed that variations had a minimal impact to product in formulation component levels within the formulation design space.
The US Food and Drug Administration's Quality by Design (QbD) initiative encourages pharmaceutical manufacturers to use modern tools that facilitate the implementation of robust manufacturing processes and reliably produce pharmaceuticals of high quality.1 Filing a new drug application (NDA) or biologics license application (BLA) under the QbD initiative may reduce the extent of regulatory oversight and may result in faster review times. Implementing a QbD approach in the development and characterization of manufacturing processes and products provides several advantages. These include a more thorough understanding of the manufacturing process and the product, as well as the potential for increased process and product robustness and process efficiency. The International Conference on Harmonization (ICH) Q82, Q93, and Q104 guidelines describe principles, tools, and examples for implementing QbD. One of these tools is the use of formal experimental designs or design of experiments (DOE) to characterize and establish a functional design space.
DOE is a tool that can be used during formulation development to screen for stabilizing excipients, determine excipient levels that provide optimal stability with adequate robustness, and characterize the formulation design space. The design space is defined in ICH Q8 as, "the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality." The formulation design space would thus define limits for the active pharmaceutical ingredient (API), excipients, pH ranges, and other critical characteristics in the formulation that maintain product stability. Because multiple formulation components are screened simultaneously, the combinations that provide optimum stability and interactions among formulation components can be identified. For example, in protein formulations that contain sodium chloride (NaCl), an interaction between pH and NaCl concentration is likely to be observed because both modulate electrostatic interactions. A DOE formulation screening study can thus help to identify optimum levels of pH and NaCl for stability.5 Similarly, in lyophilized or spray-dried protein formulations, an interaction may be observed between protein and cryo/lyoprotectant levels because an optimum ratio of the stabilizer to protein is required for cold and dehydration-induced denaturation.6,7 DOE also can be used to identify effective preservatives for multi-dose protein formulations at optimal concentrations for antimicrobial efficacy and protein stability, to characterize the effect of stress conditions and degradation pathway mechanisms in forced degradation studies, and to characterize the effect of formulation components on drug delivery systems.8–13
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The robustness of the formulated product can be characterized further in excipient robustness studies that use DOE.14,15 Excipient robustness studies performed using DOE can:
- identify critical formulation components; these are formulation components whose levels must be tightly controlled to maintain product stability or performance
- provide limits in which variations in the levels of formulation components have minimal or no effect on product stability or performance
- determine the effect on product stability of variations outside normal operating and proven acceptable ranges
- identify and characterize the interactions among formulation components
- confirm that the product is not formulated near a design space cliff or discontinuity.
Excipient robustness studies can, hence, be used to evaluate and characterize the formulation design space (Figure 1).