Importance of LC-MS analysis for Drug Development under the FDA Rule

lc ms method

LC-MS or Liquid Chromatography-Mass Spectrometry is popular and useful in pharmaceutical development. LC-MS assays offer high specificity and selectivity. In most cases, they also offer high accuracy and reproducibility.

Given the usefulness of the technique, it is fairly popular. It also plays an essential role in the bioanalytical method and drug development in general. FDA guidelines acknowledge the role of the LC MS method and instructions for its use in drug development.

Though the popular LC technique is HPLC (High-Performance Liquid Chromatography, UHPLC (Ultra-HPLC) may also be used. The conventional naming continues to call the method LC/MS or LC-MS.

The Role of LC-MS in Drug Development

LC-MS, sometimes also written as LC/MS technique, plays a major role in drug development. Its role has continued to grow and can be seen in practically every aspect of drug development. This includes drug discovery to find a potential drug candidate and all the way to human trials. It also plays an important part in bioanalytical method development and validation.

Parts of the process, such as the use in drug discovery, don’t necessarily fall under regulatory/FDA guidelines. However, much of the LC-MS analysis depends on FDA guidelines in the preclinical and later stages. LC-MS techniques are used for assay validation and bioanalytical method development and validation. Similarly, LC-MS can work as a replacement to the immunoassay or at a major complementary role.

FDA Requirements and Roles for LC-MS

The functioning of the LC-MS system can also vary with the stage of development and specific requirements. Drug discovery requires rapid, high-throughput screening that makes it possible to reach a lead candidate faster.


As the candidate drug reaches the preclinical stage, the role of LC-MS analysis becomes more focused. Regulatory requirements come into play, and various methods and analyses have to comply with the requirements. This stage forms the first point where the regulatory issues are addressed.


It is often necessary to have the LC-MS assay validated through GLP guidelines. Other assays and methods also fall under similar requirements for GLP/GMP guidelines. FDA bioanalytical method validation guidelines mention the role of the LC-MS method.


The guidelines suggest tolerance criteria for chromatographic assay of biopharmaceuticals in the validation study. This is placed at ±15% of nominal concentration and ±20% at a lower limit of quantitation.


Their effect on bioanalytical parameters like specificity and selectivity is also considered. When using this method, the FDA recommends determining the effects of the matrix on the ion suppression, ion enhancement, or extraction efficiency.


While the specific method can vary in the study, LC-MS techniques can be used in a variety of studies. These include DMPK, IND Enabling toxicology studies, and biomarkers, to name a few.


The role of this technique in clinical trials remains quite similar. It is used to analyze various sample matrices to ensure the safety, reliability, and efficacy of the drug in humans. The pharmaceutical company and the FDA discuss the presence and acceptable level of impurities during these stages. This is especially more important for the manufacturing stage.