The application of quality-by-design (QbD) principles for new chemical entities (NCEs) is highlighted in several publications. QbD, however, is rarely applied to marketed APIs. Lifecycles of existing APIs are extending. With this extension the focus on drug safety and compliance requires up-to-date knowledge of the product and its production process as over the years expectations in this respect have shifted. We applied QbD principles in order to set up an improved control strategy for the final five steps in the production route of a steroidal contraceptive, which has been produced for over 20 years within our facilities. A generic UHPLC method was developed for the quantitative analysis of the available intermediate batches which have all resulted in compliant API at full commercial scale. On the basis of the batch results, (statistically supported) specifications are proposed to create a range of proven acceptance criteria. This approach allows the application of the historical knowledge of the drug substance and its manufacturing process gained over the years to future production by exploiting the process capability of eliminating impurities and dealing with variability in the quality of the intermediates. Furthermore, it improves the process of specification setting. Generic UHPLC methods enable rapid quantitative monitoring of quality. The use of a generic UHPLC method in combination with the setup of a side-product flow scheme improves process understanding and supports chemical entity design space development. Furthermore, the use of a generic UHPLC method for multiple intermediates also offers the possibility to perform side-product tracing on the basis of retention times. A generic UHPLC method was developed according to QbD principles to create a range of proven acceptance criteria for the assay and side-product determination for the final five steps in the production route of a contraceptive API.