Quality by Design (QbD) has emerged as an element of contemporary pharmaceutical development due to the advancement of a systematic, science- and risk-based process understanding and control. The implementation of QbD is especially significant in Active Pharmaceutical Ingredient (API) production because of the complexity of the multistep processes and the necessity of the control of the quality of products and their adherence to standards. The systematic review considers the literature published in the area of QbD principles application in the optimization of processes in API manufacturing between 2005 and 2025, including Quality Target Product Profile (QTPP), Critical Quality Attributes (CQAs), Critical Material Attributes (CMAs), Critical Process Parameters (CPPs), risk assessment tools, Design of Experiments (DoE), and control strategies. The analyzed literature shows that the use of QbD leads to a robust process, increased yield, increased impurity control, and scalability and lifecycle management. Also with a scientifically justified design space, more flexibility in regulation is realized and less post-approval modifications. Although these benefits are evident, there are still difficulties of large initial investment, complexity of data and multidisciplinary skills. Altogether, this review draws major contributions to the influence of QbD on the performance of the API process and emphasizes the opportunities of its successful implementation in the future with the help of advanced analytics and digital technologies.