USA – Transitioning a Powerful Analytical Tool into Manufacturing to Improve the Quality of Complex Therapeutics

CDER researchers are evaluating an approach that would harness the potential of mass spectrometry to ensure the quality of complex protein therapeutics to treat cancer and other diseases

Mass spectrometry (MS) is a powerful analytical tool used in nearly all protein-based biologics license applications as a characterization method to assess a wide variety of protein attributes, including molecular mass, amino acid sequence, and critical chemical modifications. But despite the vast amount of information MS can provide, several barriers have stood in the way of its use for quality control (QC) of protein therapeutics (e.g., antibodies to treat cancer), including a perception that the tool is too complex for non-specialists to use in manufacturing settings.

The multi-attribute method

Recent advances in high-resolution mass spectrometry instrumentation have led to reconsideration of the use of MS for QC of protein therapeutics. Specifically, a method known as the multi-attribute method (MAM) that has allowed MS to be introduced to the quality control environment of manufacturing facilities has been developed.

In MAM, a protein product is digested into smaller units called peptides, which are then separated using a method called ultra-high-performance liquid chromatography. These peptides are then analyzed using MS, which begins by vaporizing a molecule and adding one or more electrical charges to it in a process called ionization. Once the charged peptides are inside the mass spectrometer, they are further separated according to the ratio of their mass and charge, which is measured by a detector to create a mass spectrum. Because each position on the spectrum represents a precise mass-to-charge ratio, peptides can be identified based on the known molecular masses of individual atoms. The relative amount of each peptide corresponds to its peak intensity. To obtain additional information about the protein sequence, the charged peptides can also be fragmented and further separated in an approach known as tandem MS…