Designing in Quality: Approaches to Defining the Design Space for a Monoclonal Antibody Process

How to use risk assessment strategies to integrate operations.
May 01, 2010


A systematic Quality by Design (QbD) strategy was used to develop and characterize a monoclonal antibody production process. A risk assessment approach incorporating design of experiments (DOE), especially multivariate analyses, was used to define and prioritize laboratory-scale experiments and made it possible to focus on high-risk process parameters and study the interactions of those parameters to define the design space. Scale-up/scale-down strategies, such as the effective characterization of a scale-down bioreactor model, ensured the applicability of small-scale studies, and secondary risk assessment approaches were used to ensure that various unit operations were properly integrated in the development of the design space.

Quality by Design (QbD) is a scientific, systematic, risk-based approach applied throughout a product's life cycle to ensure safe, effective products.1,2,3 In applying QbD approaches to biopharmaceutical processes that produce complex biomolecules, a systematic approach to process understanding is essential. A key goal of process understanding studies is to establish the functional relationship between the process parameters and quality attributes, including parameter interactions; therefore, process understanding invariably uses multivariate experimental strategies.

The design space, which is an output of the process understanding studies, provides a definition of process input variables and their ranges to ensure consistent quality for large-scale commercial manufacture. The continuous development of the knowledge space that ultimately makes it possible to determine the design space begins at product conceptualization, evolves in pace with product commercialization, and is ongoing throughout the product lifecycle.

Pfizer has developed a systematic approach to implementing QbD principles for process design for small molecules that encompasses process understanding, process control, and continuous improvement.4 This article explores the strategies for and challenges involved in developing a thorough process understanding and defining the design space for a monoclonal antibody manufacturing process. We briefly summarize Pfizer's strategies for systematic risk assessment to define and prioritize laboratory-scale experiments, scale-up/scale-down strategies to ensure the applicability of the small-scale studies, and secondary risk assessment approaches that integrate various unit operations.


Figure 1
The QbD process design is achieved through Pfizer's Right First Time (RFT) approach (Figure 1), which consists of achieving process understanding, process control, and continuous improvement using a life-cycle approach based on the International Conference on Harmonization (ICH) Q8, Q9, and Q10 guidelines.2,5,6 This article focuses on the first part, the development of process understanding that is used to develop the design space for a process. Commercial manufacturing processes are operated in a "control space," which is an area within the design space. A control strategy is applied to ensure that the process operation stays within the designated control space.

The QbD process design starts with an intensive characterization of the product through a large array of biochemical and biophysical analyses at normal and stressed conditions and through careful analysis of clinical and nonclinical data. This characterization provides the basis to define the criticality of product quality attributes (QAs), according to knowledge of safety and efficacy of the product. QA criticality is used to prioritize experiments for process understanding and is incorporated into the risk-assessment tools that are used.