This study is based on the idea that “quality comes from design,” that is, to systematically analyze the establishment of detection methods for related substances in pharmaceutical raw materials. At the beginning, hetero-mass spectrometry and the purpose of method development are summarized and explained, and suggestions on how to select key chromatographic parameters and how to do risk assessment are put forward. Then, the method design space is optimized by means of experimental design, and the intelligent development technology is used to make the method design more complete and efficient. The control of the chromatographic system, the influence of solvents, the integration conditions, and the detection wavelength are discussed in detail, and the corresponding control countermeasures are given. Finally, the whole life cycle of the detection of related substances is verified, and the forced degradation, sensitivity, and system applicability are taken into account. The results show that the standardized and complete development and verification ideas are conducive to ensuring the reliability of the detection method.