Darren John Schulz

A Design Space Verification Protocol for a Small Molecule Drug Substance

Regulatory expectations regarding design space verification in the designated manufacturing facility at commercial scale are not consistent across global markets. The extent and level of verification of design space boundaries are (a) predicated on the degree of risk and impact of that risk for movement within the design space and (b) are continually evaluated over the life cycle of a product and not necessarily defined as a moment in time (such as a submission date). Additionally, accommodations for differences in scientific disciplines are also important when determining design space verification strategies, for example design space verification approaches may vary between large molecule vs. small molecule drug substance, drug product, batch processes, continuous flow processes, or to assess device performance in combination products, etc. Several strategies and guiding principles to illustrate multiple opportunities and possibilities for the different disciplines to achieve design space verification using sound science and riskbased processes and procedures have recently been published [1, 2]. This publication will present a specific case study for assuring consistent quality within a design space for a recent small molecule drug substance example (of which elements are applicable across the other disciplines). It is not practical to execute and/or repeat experiments at commercial scale in a manufacturing facility to verify design space boundaries when the benefits are nebulous and the cost is prohibitive. Based on suggestions from regulatory authorities, a protocol was prepared to describe the life cycle approach and process for demonstrating design space verification. Publishing this protocol is intended to share the results of a successful interaction with regulators while continuing to facilitate open communication and opportunities for addressing the concept of design space verification. The protocol is presented within Appendix 1.