Attribute-Based Design Space: Materials-Science-Based Quality-By-Design for Operational Flexibility and Process Portability

摘要

In April, 2009, the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Product Technical Group sponsored an industry workshop to explore the practicality and limitations of defining a design space strictly in terms of material attributes rather than process variables. This material-attribute design space would be independent of scale and configuration of process equipment and the associated process variables. For this reason, it would be portable in the sense that post-approval changes of equipment scale, nameplate, or location would not require regulatory approval. This paper summarizes and expands on the output of the workshop. A key concept that underlies this work is that the performance of a drug product is determined by its structure. The control objective of a manufacturing process is to assemble the components of the product into this structure. This is achieved by controlling the attributes of raw materials and process intermediates from each step in the production train within specified ranges, i.e., by operating within a material-attribute design space. In this paper, we explore the development, implementation, and limitations of an attribute-based design space. We show that developing the design space and translating it into process conditions and manufacturing instructions for specific process trains requires the development of thorough process understanding. Thus, this concept is fully consistent with the principles of quality by design. While implementation of the concept developed in this paper is not endorsed by regulatory agencies and would require changes to relevant guidances and regulations, we believe it would provide the quality assurance required by regulators and the operational and process flexibility desired by manufacturers.