The production and use of chemicals and materials have both advantages and drawbacks for human and ecosystem health. This has led to a demand for carefully guided, safe, and sustainable innovation in the production of chemicals and materials, taking into consideration their entire life cycle. The European Commission's Joint Research Centre (JRC) has released the Safe and Sustainable by Design (SSbD) framework, which aims to support this objective. The SSbD framework consists of two components that are intended to be iteratively implemented throughout the innovation process: (1) the application of design principles phase, and (2) the safety and sustainability assessment phase. However, the operationalization of the framework is currently challenging. This article maps the challenges and proposes ways to address them effectively. The mapping, which is based on a literature review and stakeholder opinions, resulted in 35 challenges. The highest priority challenge is "integration of SSbD framework into the innovation process." To begin addressing this issue, this article recommends conducting a scoping analysis to define the SSbD study. This can be achieved through implementing a tiered approach that aligns with the objectives of the innovation and the growing expertise that comes with it. The second priority challenge is "data availability, quality and uncertainty." This can be supported by using Findability, Accessibility, Interoperability, and Reuse (FAIR) principles and by optimizing in silico methods at early stages of the innovation process. An infrastructure for data and communication is necessary to effectively engage with the entire value chain. The third priority challenge is "integration of safety and sustainability aspects," which requires a clear definition of how to integrate those aspects in the SSbD context, and harmonization, as far as possible, of input data, assumptions, and scenario construction. This review is the first step in accelerating the operationalization of the novel SSbD concept and framework into industrial practice.